Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][C:29]([N:33]([CH2:35][CH2:36][O:37][CH3:38])[CH3:34])([CH3:32])[C:30]#[CH:31]>>[CH3:32][C:29]([N:33]([CH2:35][CH2:36][O:37][CH3:38])[CH3:34])([CH3:28])[C:30]#[C:31][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:27])[F:1])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: C#CC(C)(C)N(C)CCOC
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: COCCN(C)C(C)(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and (1,1-Dimethyl-prop-2-ynyl)-(2-methoxy-ethyl)-methyl-amine were converted to yield {1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl-(2-methoxy-ethyl)-methyl-amine as brown oil, MS: 433 (MH+).
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(Cc1ccc(O)cc1)OCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
1-Adamantanemethanol (8.31 g, 0.05 mol), 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol) and p-toluenesulfonic acid (1 g, 0.006 mol) were refluxed in benzene (100 mL) with continuous water separation for 8 hours. The reaction mixture was allowed to cool with stirring overnight, then was washed, first with water (100 mL), then with aqueous 5% NaHCO3 solution (100 mL), then twice more with water (100 mL). Drying over anhydrous MgSO4, filtering and concentrating in vacuo afforded (adamant-1-yl)methyl 4-hydroxyphenylacetate, which was then combined with epichlorohydrin (50 mL) and refluxed for 2 hours in the presence of DBU (1 mL, 0.007 mol). Excess epichlorohydrin was removed in vacuo. The oily residue was dissolved in acetonitrile (100 mL) and combined with isopropylamine (20 mL, 0.23 mol). The resultant reaction mixture was refluxed for 4 hours. The oily brown residue was partitioned between ethyl ether (100 mL) and 1M aqueous KOH solution (100 mL ). The ether layer was separated and to it was added 1N HCl (30 mL). The resultant acid layer was separated and to it were added ethyl ether (100 mL) and 1M aqueous KOH solution (30 mL). The resultant ether layer was separated, dried over anhydrous MgSO4, filtered and evaporated in vacuo to give the free amine base as a crude product. The crude product (5.16 g, 72.5% yield) was dissolved in acetone (25 mL), and oxalic acid (1.8 g) in acetone (25 mL) was added dropwise, with stirring. The mixture was allowed to stir for 24 hours with additional acetone. The acetone solution was evaporated and the oily residue was partitioned between ether (100 mL) and 1M aqueous KOH solution (100 mL). The ether solution was dried over anhydrous MgSO4, filtered and concentrated. The oily residue was dissolved in acetone and an equivalent amount of oxalic acid in acetone was added dropwise. The oxalate salt of (adamant-1-yl)methyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate which separated was removed and dried. It melted at 55°-57° C. NMR and elemental analysis were consistent with structure. The free base has the formula: ##STR298##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[OH:34]/[N:33]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CC(C(=O)O)C3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CC(C(=O)O)C3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from 1-{4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-azetidine-3-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow foam, MS (ESI+): m/z=430.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([F:16])=[CH:11][C:10]=2[Cl:17])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[Ca+2].[C:23](Cl)(Cl)=[S:24]>C(Cl)CCl.O>[CH3:1][O:2][C:3]([C:5]1([S:8][C:9]2[CH:14]=[C:13]([N:15]=[C:23]=[S:24])[C:12]([F:16])=[CH:11][C:10]=2[Cl:17])[CH2:7][CH2:6]1)=[O:4]
Reactant: S=C(Cl)Cl
Reactant: COC(=O)C1(Sc2cc(N)c(F)cc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)C1(Sc2cc(N=C=S)c(F)cc2Cl)CC1
Temperature: 25 °C

Procedure:
While stirring at room temperature, a solution of 5.5 g of 1-(5-amino-2-chloro-4-fluoro-phenylthio)-cyclopropanecarboxylic acid methyl ester in 20 ml of ethylene chloride is added dropwise to a mixture of 3 g of calcium carbonate, 2 ml of thiophosgene in 20 ml of ethylene chloride and 20 ml of water. After stirring for 4 hours at room temperature, the inorganic portion of the reaction mixture is filtered off and the organic phase is dried over calcium chloride and then concentrated by evaporation, yielding 6.3 g of 1-(2-chloro-4-fluoro-5-isothiocyanato-phenylthio)-cyclopropanecarboxylic acid methyl ester having a melting point of from +100° to +101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=4)[CH:20]=3)[CH2:14][CH2:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:37][CH2:38][C:39]1[C:40]([C:45]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=2)=[N:41][CH:42]=[CH:43][CH:44]=1>>[ClH:37].[ClH:37].[ClH:37].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=4)[CH:20]=3)[CH2:16][CH2:17]2)[CH2:38][C:39]2[C:40]([C:45]3[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=3)=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1
Reactant: COc1cc(-c2ncccc2CCl)cc(OC)c1OC
Product: COc1cc(OC)cc(N(Cc2cccnc2-c2cc(OC)c(OC)c(OC)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)c1
Product: Cl

Procedure:
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. Yellow syrup obtained was converted to a trihydrochloroide to give the title compound as yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[NH:5][CH2:6][CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][C:28](=[O:33])[CH:29](Cl)[CH2:30][CH3:31]>O>[Cl:27][C:28](=[O:33])[CH:29]([N:5]([CH2:6][CH:7]=[O:8])[C:4]1[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:1][CH3:2])[CH2:30][CH3:31]
Reactant: CCc1cccc(OC)c1NCC=O
Reactant: CCC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCc1cccc(OC)c1N(CC=O)C(CC)C(=O)Cl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-ethyl-6-methoxyanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chlorobutanoyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chlorobutanoyl-2-ethyl-6-methoxyanilino)acetaldehyde.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[C@@H:13]1[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C.[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.ClCCCl>[C:16]([O:15][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:30][C@H:13]1[N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Uracil is bis-trimethylsilylated according to the procedure of Niedballa and Vorbruggeno Uracil is dissolved in benzene, and added to 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose 33.1b (Xi=β-OAc) (Niedbala and Vorbruggen) in 1,2 dichloroethane followed by tin tetrachloride in 1,2-dichloroethane according to the method of Vorbruggen and Niedballa to provide the 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)uracil 33.1b (Xi=β-uracil-1-yl). Following methanolysis with sodium methoxide in methanol the 1-(B-D-glucopyranosyl)uracil 33.1a (Xi=β-uracil-1-yl) is obtained. This is converted into the morpholino subunit 32.2b (Xi=β-uracil-1-yl) by the general procedure.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[N+:21]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH2:30][CH2:31]I)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:16]2[CH2:17][CH2:18][CH:13]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:20][CH:19]=3)=[O:12])[CH2:14][CH2:15]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(OCCCI)cc1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCCOc3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 46.2 %

Procedure:
4-(4-Methylsulfonylaminobenzoyl)piperidine hydrochloride (1.97 g, 6.19 mmol) and 1-(4-nitrophenoxy)-3-iodopropane (1.90 g, 6.19 mmol) were reacted by the procedure of Example 1 to afford 1.32 g (46%) of the desired product as a white solid: mp 162°-164° C.; 1H NMR (DMSO-d6): δ 10.29 (br s, 1H), 8.19 (d, J=9.30 Hz, 2H), 7.93 (d, J=8.86 Hz, 2H), 7.26 (d, J=8.84 Hz, 2H), 7.13 (d, J=9.31 Hz, 2H), 4.15 (t, J=6.34 Hz, 2H), 3.32 (m, 1H), 3.09 (s, 3H), 2.89 (m, 2H), 2.48 (m, 2H), 2.07 (m, 2H), 1.91 (m, 2H), 1.70 (m, 2H), 1.56 (m, 2H). IR (KBr): 3620, 3210, 2950, 1660, 1600 cm-1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:26][C:27](O)=[O:28])([CH2:6][CH:7]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH:49]1[CH2:60][CH2:59][CH2:58][C@H:50]1[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][P:4]([CH2:26][C:27]([N:49]1[CH2:60][CH2:59][CH2:58][C@H:50]1[C:51]([O:53][C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])=[O:28])([CH2:6][CH:7]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(=O)O)CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
The mono ester product from part (e) (0.81 g., 1.94 mmole) in tetrahydrofuran (4 ml.) at 0° in an argon atmosphere was treated with carbonyldiimidazole (0.31 g., 1.0 eq.). After one hour, triethylamine (0.3 ml., 1.1 eq.) then L-proline, t-butyl ester (0.43 g., 1.3 eq.) were added to the above mixture. After stirring at room temperature for 16 hours, the reaction mixture was diluted with ethyl acetate and then washed with water, 5% sodium bicarbonate, 5% potassium bisulfate (twice), brine, dried (MgSO4), and evaporated to give 0.9 g of 1-[[ethoxy[3-phenyl-2-[[(phenylmethoxy)carbonyl]amino]propyl]phosphinyl]acetyl]-L-proline, 1,1-dimethylethyl ester as a foam. Tlc (dichloromethane/acetic acid/methanol; 100/5/5) major spot at Rf =0.5.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8](Cl)=[O:9]>O1CCCC1.[Cl-].[Na+].O>[Br:2][C:3]1[CH:11]=[C:7]([C:8]([NH2:1])=[O:9])[CH:6]=[N:5][CH:4]=1
Reactant: N
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In an amount of 555 mg of 5-bromonicotinoyl chloride was dissolved in 5.5 ml of tetrahydrofuran, added with 768 μl of 28% aqueous ammonia under ice cooling, stirred for 40 minutes, then warmed to room temperature, and further stirred at room temperature for 20 minutes. The reaction system was added with 15% brine, and extracted with tetrahydrofuran, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure until about half amount of crystals were deposited, and added with ethyl acetate until the deposition of crystals was terminated, and the crystals were taken by filtration to obtain 374 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[O:24][C:23]([CH:25]([C:27]2([CH3:31])[CH2:30][O:29][CH2:28]2)[NH2:26])=[N:22][N:21]=1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:26][CH:25]([C:23]3[O:24][C:20]([CH3:19])=[N:21][N:22]=3)[C:27]3([CH3:31])[CH2:30][O:29][CH2:28]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nnc(C(N)C2(C)COC2)o1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: Cc1nnc(C(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C2(C)COC2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 48c) and (5-methyl-1,3,4-oxadiazol-2-yl)-(3-methyloxetan-3-yl)methanamine (example 245b) as starting materials and isolated (25 mg, 35%); MS (ESI, m/z): 427.7 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:34]([CH2:35][CH3:36])=[CH:33][N:32]=[C:31]([CH3:37])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([C:34]1[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:38])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:30][C:31]([CH3:37])=[N:32][CH:33]=1)[CH3:36]
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(C)cc1-c1cccc(C2=Nc3ccc(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M133) (0.26 g, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (170 mg, 87%).
Reaction SMILES: Cl[N:2]1[C:6](=O)[CH2:5][CH2:4]C1=O.[F:9][C:10]1[C:18]([I:19])=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14].O.C1(N)CC1>CN(C=O)C>[CH:6]1([NH:2][C:12](=[N:13][OH:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:18]([I:19])[C:10]=2[F:9])[CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1cccc(I)c1F
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(NC1CC1)c1cccc(I)c1F
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
N-chlorosuccinimide (1.20 g, 8.9 mmol) was added portionwise to a stirred solution of 2-fluoro-3-iodobenzaldehyde oxime (preparation 22e, 2.15 g, 8.1 mmol) in N,N′-dimethylformamide (3 mL) and the mixture was stirred for 15 minutes at 55° C. After cooling to ambient temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was taken up in tetrahydrofuran (10 mL), cooled by means of an ice-water bath and cyclopropylamine (2.90 mL, 41.9 mmol) was added dropwise. After stirring 3 hours at room temperature, water was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to give the title compound (2.53 g, 96%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(Cl)Cl.CC(O)=O.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=2)=[CH:6][CH:5]=1
Reactant: Nc1nccc(COc2ccc([N+](=O)[O-])c3ccccc23)n1
Reactant: [H][H]
Agent: [Pt]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nccc(COc2ccc(N)c3ccccc23)n1
Yield: 91.1 %

Procedure:
A solution of the nitroarene (70) (1.10 g, 3.71 mmol) in a mixture of DCM (50 mL) and AcOH (40 mL) was passed through a Thales H-cube (1.0 mL·min−1, 55 mm, 10% Pt/C, 40° C., full hydrogen mode). LC-MS analysis of the resulting solution showed a mixture comprising of mainly starting material and ca. 20% product. The DCM was removed by evaporation in vacuo and the solution re-subjected to reduction using the same conditions at RT. The volatiles were evaporated in vacuo to give the title compound (71) (ca. 70% by LC-MS) as a purple solid (0.90 g, 64% yield): m/z 267 (M+H)+ (ES+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.BrCCCC[N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([C:31]1[CH:30]=[CH:29][CH:28]=[C:25]2[C:26]([NH:22][C:23](=[O:32])[C:24]=12)=[O:27])[CH2:4][CH2:5][CH3:13].[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1cccc2c1C(=O)NC2=O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
4-(2-keto-1-benzimidazolinyl)piperidine (1.04 g, 4.79 mmol), N-(4-bromobutyl)-phthalimide (1.59 g, 5.64 mmol) and triethylamine (986 mL, 7.07 mmol) were combined in 10 mL of N,N-dimethylformamide. The reaction mixture was stirred at 50° C. for 18 hours, and then concentrated in vacuo. The residue was partitioned between dichloromethane and saturated sodium bicarbonate. The phases were separated and the organic phase was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The resulting solid was purified by “flash” chromatography (95:5:0.5 of dichloromethane:methanol:ammonium hydroxide). The product fractions were evaporated to dryness and reconcentrated twice from diethyl ether to give the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[O:7][C:6]3[C:2]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:3][S:4][C:5]=3[C:10](=[O:11])[CH:9]=2)[CH2:13][CH2:14]1
Reactant: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=c1cc(N2CCOCC2)oc2c(-c3ccccc3)csc12
Temperature: 130 °C
Yield: 2 %

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (50 mg, 0.16 mmol), phenylboronic acid (29 mg, 0.24 mmol), cesium carbonate (103 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol), and dimethoxyethane (1 mL). The reaction mixture was magnetically stirred and heated via microwave irradiation for 15 minutes at 130° C. Upon cooling to room temperature, the reaction was concentrated in vacuo and purified using high-pressure liquid chromatography to give 5-morpholino-3-phenyl-7H-thieno[3,2-b]pyran-7-one (6) (10 mg, 3.2 μmol) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][CH:38]([CH3:43])[CH2:39][CH2:40][CH2:41]O>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:41][CH2:40][CH2:39][CH:38]([CH3:43])[CH3:37])=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Reactant: CC(C)CCCO
Product: CC(C)CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-1-pentanol in place of 2-ethyl-1-hexanol (yield: 120 mg, 52%). mp 98-99° C. 1H NMR (300 MHz, DMSO-d6) δ 0.73 (d, J=7 Hz, 6H), 1.02 (m, 2H), 1.29 (m, 1H), 1.54 (m, 2H), 3.30 (s, 3H), 4.40 (t, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 463 (M+H)+; (APCI−) m/z 497 (M+Cl)−. Anal. calc. for C23H24F2N2O4S: C, 59.72; H, 5.23; N, 6.05. Found: C, 59.57; H, 5.28; N, 6.01.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[C:5]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1.C[N:16]=[C:17]=[O:18].[C:19](#N)C>>[CH3:1][N:2]1[C:6]([N:7]([CH3:19])[C:17]([NH2:16])=[O:18])=[C:5]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1
Reactant: CC#N
Reactant: CN=C=O
Reactant: Cn1nc2c(oc3ccccc32)c1N
Product: CN(C(N)=O)c1c2oc3ccccc3c2nn1C
Temperature: 25 °C

Procedure:
A solution of 2-methyl-2H-benzofuro[3,2-c]pyrazol-3-amine (4.0 g, 21.37 mmol, described in Example 6) in acetonitrile (150 mL) was combined with excess methyl isocyanate (ca. 6 mL) and the mixture was stirred at room temperature for several days. The precipitate was collected, washed with acetonitrile and diethyl ether to give the title compound (4.54 g) as off-white crystals: mp ca. 290° C. (dec.); IR (mineral oil) 3310, 3250, 1635, 1655, 1580 and 1525 cm-1 ; UV max (MeOH) 292 nm (ε=5656) and 269 (21000); NMR (DMSO-d6) δ2.65 (3H, d), 3.8 (3H, s), 6.4 (1H, m), 7.3 (3H, m), 7.8 (1H, m) and 8.35 (1H, s); and Anal. Calcd for C12H14N4O2 : C, 59.01% H, 4.95% N, 22.94% and Found: C, 58.96% H, 5.00% N, 22.62%.