Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH2:6][CH:7]=O)[C:3](=[O:5])[CH3:4].[CH:9]([NH2:11])=[O:10]>C(O)=O>[CH3:7][C:6]1[N:11]=[CH:9][O:10][C:2]=1[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)C(Cl)CC=O
Reactant: NC=O
Solvent: O=CO
Product: CC(=O)c1ocnc1C

Procedure:
Scheme IX illustrates the synthesis of compounds represented by Formula XVI. Reaction of a mixture of 3-chloro-2,5-pentanedione and formamide in refluxing formic acid yields 4-methyl-5-acetyloxazole. Reaction of the sodium salt of 4-methyl-5-acetyloxazole and diethyl oxalate in ethanol affords the corresponding ketoacetate. Reaction of the ketoacetate with hydrazine in refluxing ethanol yields 3-ethoxycarbonyl-5-[4-(methyl)oxazol-5-yl]pyrazole which is alkylated to yield isomers XXIIa and XXIIb. Substituting triethyl orthoacetate for triethyl orthoformate in the reaction described in Scheme V yields isomeric compounds represented by. Formula XVIIa and XVIIb ##STR12##
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[N:3]=1.[CH2:17]([NH2:19])[CH3:18].O>CC(C)=O>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:19][CH2:17][CH3:18])[N:3]=[C:4]([NH:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[N:5]=1
Reactant: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CCN
Solvent: CC(C)=O
Solvent: O
Product: CCNc1nc(NC(C)(C)C#N)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 5.1 grams of 4,6-dichloro-2-(1-cyano-1-methylethylamino)-5-pyrimidinecarbonitrile in 50 ml of acetone was cooled to 0° to -5°, and 2.8 grams of an aqueous solution of 70% ethylamine in 40 ml of acetone was added dropwise. The temperature of the reaction mixture was maintained at 0° to -5° throughout the addition, then during 2 hours following complete addition. The reaction mixture was warmed to room temperature where it was stirred for 1 hour. Water was added to the reaction mixture, which caused precipitation of a solid. The solid was collected by filtration and recrystallized from a mixture of benzene and methylcyclohexane to give 3.3 grams of 4-chloro-2-(1-cyano-1-methylethylamino)-6-ethylamino-5-pyrimidinecarbonitrile; mp, 157°-160°.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([NH:7][C:8](=[O:36])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:33][CH3:34])([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]([CH2:30][CH3:31])([OH:29])[CH2:27][CH3:28])=[C:20]([CH3:32])[CH:19]=2)[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])([CH3:6])[CH3:5].[OH-].[Li+]>>[CH2:16]([C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:37])=[O:2])=[O:36])=[C:10]([CH3:35])[CH:11]=1)([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]([CH2:27][CH3:28])([OH:29])[CH2:30][CH3:31])=[C:20]([CH3:32])[CH:19]=1)[CH2:33][CH3:34])[CH3:17]
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)NC(C)(C)C(=O)OC)c(C)c2)cc1C)CC
Agent: [Li+]
Agent: [OH-]
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)NC(C)(C)C(=O)O)c(C)c2)cc1C)CC
Yield: 99.5 %

Procedure:
2-(4-{1-Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-2-methyl-propionic acid methyl ester (3.97 mg, 0.785 mmol) and lithium hydroxide (56 mg, 2.36 mmol) are reacted and purified analogous to Example 1I to give the title compound (384 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:18])[CH:10]=[CH:11]C1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl.N1C=CC=CC=1>[OH:8][C:4]1[CH:3]=[C:2]2[C:7]([CH:11]=[CH:10][C:9](=[O:18])[NH:1]2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1cccc(O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1ccc2ccc(O)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-aminophenol (1 g) in CH2Cl2 (25 mL) and pyridine (1 mL) at 5° C. was added dropwise a solution of cinnamoyl chloride (1.53 g) in CH2Cl2 (10 mL). The mixture was warmed to r.t. over 1 hr, and then EtOAc (150 mL) was added. The organics were washed with H2O, 1N, HCl, saturated aq. NaHCO3 and H2O, dried (MgSO4) and concentrated. To the residue was added AlCl3 (6.38 g) and the mixture heated at 180° C. for 5 min. and then at 115°-120° C. for 2 hr. To the mixture was added ice and then H2O. The solid that formed was collected by filtration, washed with 2N HCl and H2O (3×). The resulting solid was triturated in EtOAc to provide the title compound.
Reaction SMILES: O=C=[N:3][CH:4]1[CH2:13][C:12](C)(C)[CH2:11][C:6](C)(CN=C=O)[CH2:5]1.C1(O)C=CC=CC=1.N1C=CN=C1.CCO[CH2:32][CH2:33][O:34][C:35](C)=[O:36].C(N(CCO)CCO)CCC.C(C1OC1)Cl.C(OS(OCC)(=O)=O)C>C(O)C>[C:4]1([NH:3][C:35]([O:34][CH2:33][CH3:32])=[O:36])[CH:13]=[CH:12][CH:11]=[CH:6][CH:5]=1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: CCOCCOC(C)=O
Agent: CCCCN(CCO)CCO
Agent: CCOS(=O)(=O)OCC
Agent: c1c[nH]cn1
Solvent: Oc1ccccc1
Solvent: ClCC1CO1
Solvent: CCO
Product: CCOC(=O)Nc1ccccc1

Procedure:
1.0 mol of isophorone diisocyanate is dissolved in 2.2 mol of phenol at 95°-100° C. after the addition of 0.5 imidazole. The mixture is kept as a liquid by the addition of 200 ml of ethylglycol acetate. 0.9 mol of butyldiethanolamine are added after a reaction time of four hours and the mixture is then distilled at a reaction temperature of 120° C. to remove everything which distils off at a vacuum of 5 torr. The residue is then dissolved in 200 ml of ethylglycol acetate and 400 ml of ethanol and quaternised at 60°-70° C., first with 0.5 mol of epichlorohydrin for three hours and then with 0.5 mol of diethylsulphate. The readily soluble cationic polyurethane with phenylurethane end groups obtained in this way is made up to a volume of 2000 ml with methanol and then stored at temperatures below 10° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:11]([C:13]1[O:17][N:16]=[C:15]([CH2:18][CH3:19])[N:14]=1)[OH:12])[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[NH2:7][CH:8]([CH2:9][CH3:10])[C@@H:11]([C:13]1[O:17][N:16]=[C:15]([CH2:18][CH3:19])[N:14]=1)[OH:12]
Reactant: CCc1noc(C(O)[C@H](CC)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1noc([C@@H](O)C(N)CC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {(S)-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)-hydroxy-methyl]-propyl}-carbamic acid tert-butyl ester (3.67 g, 12.87 mmol) in dichloromethane (50 mL) was treated with trifluoroacetic acid (10 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with toluene then evaporated under vacuum to dryness. The residue was dissolved in dichloromethane (75 mL) and the solution was treated with MP-Carbonate (3.3 mmol/g, 6.0 g). This mixture was stirred at room temperature overnight, then filtered, then washed with 10% dichloromethane methanol and evaporated under vacuum to give (S)-2-amino-1-(3-ethyl-1,2,4-oxadiazol-5-yl)-butan-1-ol, a mixture of diastereomers, (2.26 g). 1H NMR [(CD3)2SO]: δ 4.61 and 4.54 (d, J=5 Hz, 1H), 2.86 (m, 1H), 2.71 (q, J=8 Hz, 2H), 1.6–1.0 (2×m, 2H), 1.22 (t, J=8 Hz, 3H), 0.88 (m, 3H). MS m/z 186 (M+H).
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]([Cl:14])=[CH2:13])(=[O:9])[CH:2](C(C([O-])=O)O)[OH:3].I(O)(=O)(=O)=O>C(OCC)C>[OH2:3].[C:1]([O:10][CH2:11][C:12]([Cl:14])=[CH2:13])(=[O:9])[CH:2]=[O:3]
Reactant: C=C(Cl)COC(=O)C(O)C(O)C(=O)[O-]
Agent: [O-][I+3]([O-])([O-])O
Solvent: CCOCC
Product: C=C(Cl)COC(=O)C=O
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 333.4 %

Procedure:
To a solution of 6.3 g (0.021 mole) 2-chloroallyl tartarate in 300 ml ethyl ether was added 5.02 g (0.022 mole) periodic acid and the mixture was stirred for two hours at room temperature. The mixture was filtered and the filtrate evaporated to afford 5.83 g (83%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[Br:24][C:25]1[CH:26]=[C:27]([O:30][CH:31]=1)[CH:28]=O>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:28]([C:27]3[O:30][CH:31]=[C:25]([Br:24])[CH:26]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: O=Cc1cc(Br)co1
Reactant: Nc1cc(Br)cc(N)n1
Product: Nc1cc(Br)cc2nc(-c3cc(Br)co3)nn12

Procedure:
The title compound, MS m/e (%): 359 (M++1, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 4-bromo-furfural. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([Cl:25])(=[O:24])[CH3:23]>>[ClH:25].[C:22]([N:19]1[CH2:20][CH2:21][C:8]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:17][CH2:18]1)(=[O:24])[CH3:23]
Reactant: c1ccc(-c2c3c(nc4ccccc24)CCNCC3)cc1
Reactant: CC(=O)Cl
Product: CC(=O)N1CCc2nc3ccccc3c(-c3ccccc3)c2CC1
Product: Cl
Yield: 90 %

Procedure:
3-Acetyl-1,2,4,5-tetrahydro-11-phenyl-3H-azepino[4,5-b]quinoline hydrochloride was prepared from 1,2,4,5-tetrahydro-11-phenyl-3H-azepino[4,5-b]quinoline and acetyl chloride analogous to Example 63.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1)(=[O:31])=[O:30].[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: CCC(=O)O
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cl
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3ccccc3F)cc2c2cc[nH]c12
Yield: 44.1 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 28 μL (0.21 mmol) of 2-fluoro-benzenesulfonyl chloride. After recrystallization from methanol, 38 mg (45%) of 8-(2-fluoro-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a light brown solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11]N)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:13]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[C:13]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]=1[NH:11]2)([O-:4])=[O:3]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: O=C1CCCCCCC1
Agent: Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2[nH]c3c(c12)CCCCCC3
Yield: 32.7 %

Procedure:
3-Nitrophenylhydrazine hydrochloride (50 g, 0.26 mol) and cyclooctanone (32.2 g, 0.25 mol) were refluxed in 400 mL of glacial acetic acid for 6 hours. The solution was allowed to cool and the separated solid was filtered, washed with water and recrystallized from absolute ethanol to afford 20 g (31% yield) of 6,7,8,9,10,11-hexahydro-1-nitro-5H-cyclooct[b]indole; m.p. 189°-191° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:4]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:4]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: COCCNc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCNc1c(N)ccc(F)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.4 %

Procedure:
A solution of (3-fluoro-6-nitro-2-pyridin-2-yl-phenyl)-(2-methoxyethyl)amine (414 mg, 1.4 mmol) in EtOAc (5 mL) was added to a slurry of palladium on carbon (10% by wt, 41 mg) in EtOAc (5 mL) under nitrogen. The reaction mixture was stirred at RT under an atmosphere of hydrogen for 4 h. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to give the title compound as a yellow oil (382 mg, 99%). LCMS (Method C): RT 1.92 min [M+H]+ 262. 1H NMR (CDCl3, 400 MHz): δ 8.72 (1H, ddd, J=5.0, 2.0, 1.0 Hz), 7.77, (1H, ddd, J=8.0, 8.0, 2.0 Hz), 7.60-7.56 (1H, m), 7.26 (1H, ddd, J=7.5, 5.0, 1.0 Hz), 6.73-6.66 (2H, m), 5.67 (1H, bs), 3.86 (2H, bs), 3.18-3.16 (2H, m), 3.01 (3H, s), 2.96-2.93 (2H, m)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:22][C:23](=[O:28])[CH2:24][CH2:25][C:26]#[CH:27])[CH2:19][CH2:20][CH3:21]>CCN(CC)CC.[Cu]I>[CH2:18]([O:22][C:23](=[O:28])[CH2:24][CH2:25][C:26]#[C:27][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:7]=1)[CH2:19][CH2:20][CH3:21]
Reactant: COc1ccc(CNc2cccc(Br)n2)cc1
Reactant: C#CCCC(=O)OCCCC
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CCC#Cc1cccc(NCc2ccc(OC)cc2)n1
Reaction time: 12 h
Yield: 79.6 %

Procedure:
To a mixture of 6-2 (8.64 g, 29.48 mmol) and 6-4 (5.0 g, 32.4 mmol) in Et3N (50 mL) at 0° was added CuI (0.14 g, 0.74). The solution was purged with argon and [(C6H5)3P]2PdCl2 (0.52 g, 0.74 mmol) was added. After 1 h the cooling bath was removed and the solution was stirred for an additional 12 h. The solution was diluted with diethyl ether (250 mL) and washed with water (4×100 ml) followed by brine (100 mL). The etheral layer was dried (Na2SO4), concentrated, and chromatographed (silica gel, 30% ethyl acetate/hexanes) to give 8.6 g of 6-5.
Reaction SMILES: FC1[CH:3]=[C:4](C=CC=1F)[C:5](O)=[O:6].CC1([C:18]2[CH:31]=[CH:30][C:21]([O:22][C:23]3[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)=[CH:20][CH:19]=2)OCCO1>>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:21]2[CH:20]=[CH:19][CH:18]=[C:31]3[C:30]=2[CH2:3][CH2:4][C:5]3=[O:6])=[N:28][CH:27]=1
Reactant: CC1(c2ccc(Oc3ccc(N)cn3)cc2)OCCO1
Reactant: O=C(O)c1ccc(F)c(F)c1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 3,4-difluorobenzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 6-[4-(2-methyl-1,3-dioxolane-2-yl)phenoxy]-3-pyridinylamine obtained in Reference Example 35 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:20])[CH3:19])=[C:13]([CH3:21])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br-:22].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:20])[CH2:19][Br:22])=[C:13]([CH3:21])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [Br-]
Reactant: CC(=O)c1c(C)cc(Oc2ccc3c(c2)OCO3)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(Oc2ccc3c(c2)OCO3)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.2 %

Procedure:
To a solution of 1-(4-(benzo(d)(1,3)dioxol-5-yloxy)-2,6-dimethylphenyl)ethanone (4.80 g, 16.9 mmol) in acetonitrile (33.8 mL) was added tetrabutylammoniumtribromide (TBABr3, 8.14 g, 16.9 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 1-(4-(benzo(d)(1,3)dioxol-5-yloxy)-2,6-dimethylphenyl)-2-bromoethanone (6.70 g), which was used directly for the next step without further purification.
Reaction SMILES: CS([Cl:5])(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[C:9]([CH3:15])[CH:8]=1.C(N(CC)CC)C.O>ClCCl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:5])=[C:9]([CH3:15])[CH:8]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
Methanesulfonyl chloride (6.83 mL, 88.3 mmol) is added slowly to a solution of (4-bromo-2-methyl-phenyl)methanol (16.14 g, 80.27 mmol) and triethylamine (16.78 mL; 120.4 mmol) in dichloromethane (80.7 mL) cooled in ice/water. The mixture is allowed to slowly warm to ambient temperature and is stirred for 16 hours. Further methanesulfonyl chloride (1.24 mL; 16.1 mmol) is added and the mixture is stirred at ambient temperature for 2 hours. Water (80 mL) is added and the phases are separated. The organic layer is washed with hydrochloric acid (1N; 80 mL) then saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na2SO4 Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane) to give the title compound (14.2 g; 80.5% yield). 1H NMR (300.11 MHz, CDCl3): δ 7.36-7.30 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 4.55 (s, 2H), 2.41 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:5][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:16]([OH:18])=O)=[N:10][C:11]=2[O:12][CH2:13][CH2:14][F:15])[CH2:3]1.Cl.[F:21][C:22]1([F:30])[CH2:26][NH:25][C@H:24]([C:27]([NH2:29])=[O:28])[CH2:23]1>>[F:19][C:2]1([F:1])[CH2:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:16]([N:25]3[CH2:26][C:22]([F:30])([F:21])[CH2:23][C@H:24]3[C:27]([NH2:29])=[O:28])=[O:18])=[N:10][C:11]=2[O:12][CH2:13][CH2:14][F:15])[CH2:5]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCCF)n1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCCF)n1
Yield: 43.3 %

Procedure:
In analogy to the procedure described in Example 127 e), 5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxyl)pyridine-2-carboxylic acid (Example 147 c, 25 mg, 90.5 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 20.3 mg, 109 μmol) to obtain the title compound (16 mg, 43%) as off-white solid, MS (ESI): m/e=409.1304 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][NH2:28]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[N:28]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(Br)cc1)C(F)(F)C(F)(F)F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1
Temperature: 125 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
1-(4-Bromo-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (8.0 g, 24.3 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (5.7 g, 31.6 mmol) were added to acetic acid (116.0 mL). The reaction mixture was stirred at 125° C. for 4 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 8.5 g of the titled compound as a yellow liquid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[N:22]1[CH:27]=[CH:26][C:25]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccncc1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccncc2)s1
Yield: 16 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and pyridine-4-boronic acid (7 mg, 0.06 mmol). The title compound was obtained in 16% yield (3.1 mg). MS (ESI+) calcd mass for C16H12N6O2S2 384.046315, found 384.047755.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:28])=[C:22]([CH:24]=[CH:25][C:26]=1[Cl:27])[NH2:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>C(O)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:28])=[C:22]([N:23]2[CH:31]=[CH:35][CH:34]=[CH:33]2)[CH:24]=[CH:25][C:26]=1[Cl:27])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(N)c1Cl)(c1ccccc1)c1ccccc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2)c1Cl)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of 3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichloroaniline (6.08 g) in acetic acid (15 ml) was added 2,5-dimethoxytetrahydrofuran (1.87 g). The mixture was stirred at 90° C. for 1 hour and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluted with n-hexane-ethyl acetate to give 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (5.82 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH3:28][NH2:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24](=[O:26])[NH:29][CH3:28]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: CN
Product: CNC(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with methylamine at 22° C. to give the title compound as a white solid. MS: 389.1 ([M−H]−).
Reaction SMILES: [Br:1][C:2]([Br:14])(Br)[C:3]([C@H:5]1[C:7]([CH3:9])([CH3:8])[C@H:6]1[C:10]([OH:12])=[O:11])=O.[BH4-].[Na+]>O>[Br:1][CH:2]([Br:14])[CH:3]1[CH:5]2[CH:6]([C:7]2([CH3:9])[CH3:8])[C:10](=[O:12])[O:11]1
Reactant: CC1(C)[C@H](C(=O)C(Br)(Br)Br)[C@@H]1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC1(C)C2C(=O)OC(C(Br)Br)C21

Procedure:
Cis 2-tribromoacetyl-3,3-dimethylcyclopropane carboxylic acid (0.2 mmol) prepared by a method analogous to that described in Example 1, was stirred for 10 minutes with a solution of sodium borohydride (0.8 mmol) in 5 ml water at room temperature for 16 hours and the crystalline reaction product was then filtered off and dried under reduced pressure at 40° C. The resulting product weighed 13 mg and contained 50% of the desired product, largely in the form of the endo isomer.