Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5](Br)=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[Mg].Br[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1>O1CCCC1.C(OCC)(=O)C>[S:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Brc1cccs1
Reactant: CCCCCCCCOc1cc(Br)c(OCCCCCCCC)cc1Br
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCOc1cc(-c2cccs2)c(OCCCCCCCC)cc1-c1cccs1
Yield: 45 %

Procedure:
A solution of 1,4-dibromo-2,5-dioctyloxybezene (6.580 grams, 13.365 mmol) in 15 milliliters of anhydrous tetrahydrofuran (THF) was added slowly over a period of 20 minutes to a mechanically stirred suspension of magnesium turnings (0.975 gram, 40.095 mmol) in 5 milliliters of THF in a 250 milliliter round-bottomed flask under an inert argon atmosphere. The resultant mixture was stirred at 60° C. for 3.5 hours. Subsequently, the resulting mixture was added to a mixture of 2-bromothiophene (5.447 grams, 33.412 mmol) and [1,3-bis(diphenylphosphinoethane]dichloronickel (II) (0.350 gram, 0.663 mmol) in 45 milliliters of anhydrous THF in a 250 milliliter round-bottomed flask under an inert atmosphere, and refluxed for 24 hours. Thereafter, the reaction mixture was diluted with 200 milliliters of ethyl acetate, washed twice with water and then dried with anhydrous magnesium sulfate. A brown solid, obtained after evaporation of the solvent, was purified by column chromatography on silica gel and recrystallization yielding 1,4-bis(2-thienyl)-2,5-dioctyloxybenzene as a light yellow crystalline product in 45 percent yield.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[F:20])[N:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3].[OH-].[Na+]>CC(O)=O.C(O)(C(F)(F)F)=O>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[F:20])[N:16]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCOc1cc2ccn(-c3ccc(Cl)cc3)c2cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C)CCCCOc1cc2c(cc1F)N(c1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
A solution of 25 mg (0.67 mol) Allyl-{4-[1-(4-chloro-phenyl)-6-fluoro-1H-indol-5-yloxy]-butyl}-methyl-amine in 1 ml AcOH/TFA (1:1) was treated at 0° C. with 70 mg (1.11 mmol) NaBCNH3 and stirred at room temperature for 8 hours. The mixture was poured into icy 2M NaOH and extracted three times with Et2O. Evaporation of the solvent, drying with MgSO4 and column chromatography on silica gel with CH2Cl2/MeOH/NEt3 10:1:0.1 gave 20 mg (80%) Allyl-{4-[1-(4-chloro-phenyl)-6-fluoro-2,3-dihydro-1H-indole-5-yloxy]-butyl}-methyl-amine, MS: 389 (MH+).
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1.Br[CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([N+:28]([O-:30])=[O:29])=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:24]=2[CH:37]=1>C(O)C>[N+:28]([C:26]1[O:27][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][O:5][C:6]3[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=3)=[CH:37][C:24]=2[C:25]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1cccc(OCc2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)c1

Procedure:
To a solution of 0.0066 ml. of sodium ethoxide in 50 ml. of ethanol is added 1.2 g. (0.0066 mole) of ethyl 3-hydroxyphenylacetate. The mixture is heated at its reflux temperature for three hours, then 2 g. (0.006 mole) of 5-bromomethyl-2-nitro-3-phenylbenzofuran is added. The mixture is heated at its reflux temperature for 16 hours. On cooling of the reaction mixture a yellow precipitate is obtained which is separated by filtration. Recrystallization from a mixture of hexane and benzene provides ethyl 3[(2-nitro-3-phenylbenzofuran-5-yl)methoxy]phenylacetate, m.p. 67°-68° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperazine-1-carboxylate (0.0394 g, 0.0983 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0131 g, 0.0894 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-ynyl)piperazine-1-carboxylate (0.0315 g, 66%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]([NH2:8])=[C:3]([OH:9])[CH:2]=1.Cl.Cl.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](O)=O.[OH-].[Na+]>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22]1[O:9][C:3]2[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][C:4]=2[N:8]=1
Reactant: Nc1ccc(O)c(N)c1
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2oc(-c3ccc4ccccc4c3)nc2c1
Temperature: 180 °C
Reaction time: 3.5 h
Yield: 74.9 %

Procedure:
80 μmol of 2,4-diaminophenol.2HCl and 80 μmol of naphthalene-2-carboxylic acid were dissolved in 100 mg of PPA, and then, the mixed solution was stirred at a temperature of 180° C. for 3 to 4 hours. After completion of the reaction, the reaction solution was cooled, neutralized with 10% NaOH, and filtered by using distilled water for recrystallization in a slow manner, thereby obtaining 15.6 mg of 2-(naphthalene-2-yl)benzo[d]oxazole-5-amine (Derivative #3) (yield: 75%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:15]([N:17]([CH:31]([CH3:33])[CH3:32])[C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[O:16])[C:12]([CH3:14])=[CH:13][C:8]=2[O:7][C:6]([CH3:35])([CH3:34])[C:5]1=[O:36].[H-].[Na+].CN(C)C=O.[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>O>[CH:31]([N:17]([C:15]([C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[O:7][C:6]([CH3:34])([CH3:35])[C:5](=[O:36])[N:4]([CH2:3][CH2:2][O:1][C:44](=[O:47])[CH2:45][CH3:46])[C:9]=2[CH:10]=1)=[O:16])[C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19]1)([CH3:32])[CH3:33]
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCO)C(=O)C(C)(C)O2
Reactant: CCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)OCCN1C(=O)C(C)(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (3R)-3-[{[4-(2-hydroxyethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (150 mg) were added sodium hydride (16 mg) and N,N-dimethylformamide (9 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added propionic chloride (0.03 ml), and the mixture was further stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (110 mg) as a colorless liquid.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].O=[CH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21]>>[CH2:1]([N:4]([CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21])[CH2:2][CH3:3]
Reactant: CCCNC1CCc2ncsc2C1
Reactant: O=CCCCNC(=O)N1CCN(c2ccccc2)CC1
Product: CCCN(CCCCNC(=O)N1CCN(c2ccccc2)CC1)C1CCc2ncsc2C1
Yield: 68 %

Procedure:
Compound 61 is prepared from 1C and 61C as described for 1. The salt of maleic acid is crystallized from acetonitrile/diethylether.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:19]1([C:24](O)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:24]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:25])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: O=C(O)C1CCCC1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)C2CCCC2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (100 mg, 0.41 mmol), cyclopentane carboxylic acid (46 mg, 0.41 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylaminopyridine (55 m g, 0.45 mmol) in dry dichloromethane (2.5 ml) were stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated to obtain 40 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)cyclopentanecarboxamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 0.5 ml). 1H NMR (DMSO) 9.98-10.09 (bs, 1H), 7.93 (t, 1H), 7.37 (d, 1H), 7.20 (s, 1H), 7.0 (d, 1H), 4.59-4.63 (m, 1H), 4.2-4.3 (m, 1H), 4.07-4.15 (m, 2H), 3.73-3.84 (m, 2H), 3.07-3.15 (m, 2H), 2.99 (s, 3H), 2.59-2.68 (m, 2H), 2.4-2.48 (m, 1H), 2.38 (s, 3H), 1.4-1.84 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12>>[CH2:11]([O:10][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[C:13]([C@H:14]1[CH2:22][CH:21]=[CH:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:23])[CH3:12]
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: CCOc1ccccc1OCC
Product: CCOc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OCC

Procedure:
Prepared from 1,2-Diethoxybenzene and cis-1,2,3,6-tetrahydrophthalic anhydride as described for compound A3. M.p. 125-127° C.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH2:4][OH:5].[H-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12](F)=[N:13][CH:14]=1>CN(C=O)C.CC(=O)OCC>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:5][CH2:4][CH:2]2[CH2:3][CH2:1]2)=[N:13][CH:14]=1
Reactant: Fc1ccc(Br)cn1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-cyclopropyl-methanol (6.15 g) and DMF (12 mL) was added NaH (60% in mineral oil, 1.5 g) at 0° C. After stirring for 4 hours at r.t. the mixture was diluted with DMF (5 mL) and 5-bromo-2-fluoro-pyridine (6.00 g) was slowly added keeping the reaction temperature below 30° C. After 30 minutes at r.t. the mixture was heated to 130° C. for 1 hour by microwave irradiation. After cooling to r.t. the mixture was diluted with EA and washed with water (3 times). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by SGC to provide the subtitle compound. MS ESI+: m/z=228 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]1[CH2:13][O:12]1.C(O)(=O)C(O)=[O:16].O1CCOCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:16])([OH:12])[CH3:13]
Reactant: O=C(O)C(=O)O
Reactant: Clc1ccc(CCC2CO2)c(Cl)c1
Solvent: C1COCCO1
Solvent: O
Product: CC(O)(O)CCc1ccc(Cl)cc1Cl

Procedure:
A mixture of 50 parts of [2-(2,4-dichlorophenyl)ethyl]-oxirane, 7 parts of ethanedioic acid, 300 parts of 1,4-dioxane and 150 parts of water is stirred and refluxed for 36 hours. The reaction mixture is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried at the air, yielding 1-[2-(2,4-dichlorophenyl)ethyl]ethanediol; mp. 83.2° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:36])=[C:31]([CH:35]=1)[C:32](Cl)=[O:33].C(O)C(N)(CO)CO>ClCCCl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:36])=[C:31]([CH:35]=1)[C:32]([NH:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)=[CH:5][CH:6]=1)=[O:33]
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: Cc1ccc(F)cc1C(=O)Cl
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(N2CC[C@@H](N3CCC[C@@H]3C)C2)nc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.1 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of 5-fluoro-2-methyl-benzoyl chloride (47 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 10.4 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH2:55]([S:57](Cl)(=[O:59])=[O:58])[CH3:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([S:57]([CH2:55][CH3:56])(=[O:59])=[O:58])[CH2:49][CH2:48]1)=[O:53]
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and ethanesulfonyl chloride as the starting materials in 60% yield. LCMS for C25H29ClN7O4S (M+H)+: m/z=558.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13])[CH2:11][O:10]1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13]
Reactant: CCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane (4.3 g, 0.016 mol) in DMSO (50 ml), 1,2,4-triazole (2.98 g, 0.043 mol) and potassium carbonate (5.96 g, 0.043 mol) were added, followed by stirring at 60° C. for 2 hours. After the completion of the reaction, water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether-ethyl acetate, whereby 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (1.5 g, yield: 25%) was obtained as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CCN(CC)CC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]1([S:22]([NH:5][C:4]2[CH:3]=[C:2]([I:1])[CH:8]=[CH:7][CH:6]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(I)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 3-iodoaniline (5 g, 22.8 mmol), in CH2Cl2 (100 mL), were added at room temperature Et3N (6.97 mL) followed by benzenesulfonyl chloride (5.84 mL). The mixture was stirred 4 h then a white precipitate was formed. A saturated aqueous solution of NaHCO3 was added and the phases were separated. The aqueous layer was extracted several times with CH2Cl2 and the combined extracts were dried over (MgSO4) then evaporated. The crude mixture was dissolved in MeOH (100 mL) and NaOMe (6 g), was added and the mixture was heated 1 h at 60° C. The solution became clear with time and HCl (1N) was added. The solvent was evaporated under reduced pressure then the aqueous phase was extracted several times with CH2Cl2. The combined organic extracts were dried over (MgSO4) and evaporated. The crude material was purified by flash chromatography using (100% CH2Cl2) as solvent yielding the title compound 21 (7.68 g, 94%) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]O>S(Cl)(Cl)=O.ClCCl>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[C:3]=1[F:11]
Reactant: O=C(O)c1ccnc(Cl)c1F
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
2-Chloro-3-fluoroisonicotinic acid (3.30 g, 18.8 mmol) was suspended in thionyl chloride (40 ml) and heated under reflux for 2.5 h. The solvent was evaporated and the residue dried by means of azeotropic removal of water with toluene (100 ml) to afford a pale yellow oil. The oil was dissolved in dichloromethane (20 ml) and cooled to 0° C. before methanol (2.42 g, 75.3 mmol) was added dropwise to the solution over 15 min. On complete addition the mixture was allowed to warm to ambient temperature and stirred for 18 h. The solvent was evaporated and the mixture partitioned between water (75 ml) and dichloromethane (100 ml). The aqueous phase was extracted further with dichloromethane (100 ml), the organic layers were combined, washed with brine (75 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give 2-chloro-3-fluoroisonicotinic acid methyl ester (3.32 g, 93%) as a pale yellow solid: δH (360 MHz, CDCl3) 3.99 (3H, s), 7.70 (1H, dd, J 5 and 5), 8.31 (1H, d, J 5).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:19][C:15]1[C:16]([F:18])=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[C:13]([N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)[CH:14]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 482 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.30-6.85 (m, 7H), 4.90-2.70 (m, 5H), 1.90-0.65 (m, 8H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:26]([O:30][C:31]([C:33]1([CH2:37][NH2:38])[CH2:36][CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CCO>[C:26]([O:30][C:31]([C:33]1([CH2:37][NH:38][C:3]([C:5]2[N:6]=[C:7]([C:24]#[N:25])[C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])[CH2:34][CH2:35][CH2:36]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)C1(CN)CCC1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3c(=O)n(Cc4ccccc4)ccc3c2O)CCC1
Temperature: 140 °C
Yield: 87.3 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.075 mmol) and 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (55 mg, 0.30 mmol) in EtOH (2 mL) was heated at 140° C. in a microwave reactor for 2 h. Solvent was evaporated in vacuo, and the residue was purified by chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 32 mg of the title compound as a viscous oil. MS: (+) m/z 489.33 (M+1).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[C:8](Cl)[S:7][N:6]=1)[CH:2]=[CH2:3].NC(N)=[S:13].O1CCCC1>O>[CH2:1]([S:4][C:5]1[N:9]=[C:8]([SH:13])[S:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: NC(N)=S
Reactant: C=CCSc1nsc(Cl)n1
Solvent: C1CCOC1
Solvent: O
Product: C=CCSc1nsc(S)n1
Reaction time: 8.5 h
Yield: 57.4 %

Procedure:
A mixture of 3-allylthio-5-chloro-1,2,4-thiadiazole (15.0 g), thiourea (5.95 g), tetrahydrofuran (45 ml) and water (15 ml) was gently boiled for 8.5 hours at 65° C. The reaction mixture was post-treated according to conventional manner to give powder of 3-allylthio-1,2,4-thiadiazole-5-thiol (8.5 g), mp. 107° to 108° C.