Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[CH:5]=1.CC(C[AlH]CC(C)C)C>ClCCl.C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[OH:11]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCc1ccc(Br)c(O)c1
Reaction time: 2.75 h

Procedure:
To a suspension of 4-bromo-3-hydroxybenzoic acid methyl ester 70 (6.97 g, 30.2 mmol) in dichloromethane (360 mL) at 0° C. was added DIBALH (100 mL of a 1 M in toluene, 100 mmol) portionwise. Significant gas evolution was observed. The resultant mixture was warmed to room temperature and stirred for 2.75 h. After this time, the reaction mixture was quenched by the addition of saturated aqueous sodium potassium tartrate (600 mL) and saturated aqueous ammonium chloride (100 mL). The resultant biphasic mixture was stirred vigorously for 2 h, and then extracted with dichloromethane (3×). The organic layers were dried over Na2SO4 and filtered, to give 71. 1H NMR (400 MHz CDCl3) δ: 1.70 (br s, 1H), 4.64 (d, J=4.5 Hz, 2H), 5.55 (br s, 1H), 6.82 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H). MS (EI) m/z (M−H−) 201.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([C:28]5[S:29][C:25]([CH3:24])=[CH:26][CH:27]=5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: Cc1ccc(C(=O)O)s1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc(C)s4)nc3cc21

Procedure:
5-Methyl-thiophene-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 5-methylthiophen-2-carboxylic acid (125 mg, 0.89 mmol). The title compound was obtained as yellow powder (166 mg, 47%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][C:2]=1[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[Cl-].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH3+:27])[CH:22]=[C:21]2[CH3:28].CCN(C(C)C)C(C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH:27][C:7]([C:5]1[CH:4]=[N:3][C:2]([C:10]3[N:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:1][CH:6]=1)=[O:9])[CH:22]=[C:21]2[CH3:28]
Reactant: O=C(O)c1cnc(-c2ncccn2)nc1
Reactant: Cc1cn([NH3+])c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(NC(=O)c2cnc(-c3ncccn3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A mixture of [2,2′]bipyrimidinyl-5-carboxylic acid (166 mg, 0.82 mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (164 mg, 0.82 mmol) and DIPEA (106 mg, 0.82 mmol) in DMF (5 mL) is stirred at rt for 5 min. 4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride (226 mg, 0.82 mmol) is added. The reaction mixture is heated to 50° C. for 1.5 h and then concentrated in vacuo. The residue is taken up in DMSO-d6 and then purified via reverse phase C18 HPLC chromatography eluting with water and acetonitrile containing 0.1% TFA buffer to afford [2,2]bipyrimidinyl-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (56%). MS: 349 (M+H); 1H NMR (300 MHz, CDCl3): δ=2.27 (s, 3H), 7.05 (dt, 1H), 7.33 (s, 1H), 7.36 (dd, 1H), 7.42-7.46 (m, 1H), 7.72 (t, 1H), 9.07 (d, 2H), 9.51 (s, 2H), 12.17 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].Br[CH2:32][CH2:33][CH2:34][Cl:35].O>CN(C)C=O>[Cl:35][CH2:34][CH2:33][CH2:32][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCl)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
814 mg (2.09 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 15 ml of dimethylformamide under argon atmosphere, 256 mg of sodium hydride (60% oil dispersion) and 0.42 ml of 1-bromo-3-chloropropane were added under ice-cooling and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to give 193 mg (20%) of 5-(3-chloropropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:24](O)=[O:25])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25])([O-:20])=[O:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)c([N+](=O)[O-])c4)cc23)CC1
Yield: 62.8 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 26.4 mg (0.131 mMol) 3-nitro-4-chlorobenzoic acid, 11.4 mg (63.3%) of the title compound were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.BrC1C=CC(I)=C(S(C)(=O)=O)C=1.[Cl:30]C1C=C(B(O)O)C=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:30])[CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Agent: CS(=O)(=O)c1cc(Br)ccc1I
Product: CS(=O)(=O)c1cc(Br)ccc1-c1cccc(Cl)c1

Procedure:
Following the general method as outlined in Intermediate 203, starting from 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202) and 3-chlorophenylboronic acid, the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])[CH:4]=[CH:3]1.Br[C:31]1C=CC=C2C=1C=CN2.CI.BrCCCCC>>[CH3:31][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])=[CH:6]1
Reactant: O=C1N(Cc2ccc(=O)[nH]c2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Brc1cccc2[nH]ccc12
Solvent: CI
Solvent: CCCCCBr
Product: Cn1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)ccc1=O

Procedure:
Following the procedure described in PREPARATION 1A, and making non-critical variations using 1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4-bromoindole, and methyl iodide to replace 1-bromopentane, the title compound was obtained (78%): mp 115-118° C.; 1H NMR (300 MHz, CDCl3) δ 7.39-7.23 (m, 3H), 7.18 (d, 1H), 7.06 (t, 1H), 6.87 (d, 1H), 6.57-6.48 (m, 2H), 6.02 (s, 1H), 5.87-5.83 (m, 2H), 4.90 (d, 1H), 4.75-4.52 (m, 3H), 3.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.8, 162.5, 155.9, 149.1, 142.4, 141.6, 139.7, 137.6, 132.1, 129.1, 124.4, 123.9, 121.3, 119.1, 114.0, 108.6, 102.8, 101.6, 93.7, 80.3, 58.2, 40.8, 38.0; MS (ES+) m/z 403.3 (M+1).
Reaction SMILES: [C:1]1(O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]([O-:12])([O-])([O:9][CH3:10])[CH3:8]>>[CH2:3]([C:1]1[C@@H:5]([CH2:8][C:7]([O:9][CH3:10])=[O:12])[CH2:4][CH2:3][CH:2]=1)[CH2:2][CH2:1][CH2:5][CH3:4]
Reactant: COC(C)([O-])[O-]
Reactant: OC1=CCCC1
Product: CCCCCC1=CCC[C@@H]1CC(=O)OC

Procedure:
Process according to claim 8, wherein said cyclopentenol is reacted with methyl orthoacetate in the presence of pyvalic acid to provide (+)-methyl (1R)-2-pentyl-2-cyclopentene-1-acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][O:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1
Reactant: CS(=O)(=O)OCc1ccco1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 491 mg (2.00 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 0.35 g (2.00 mmol) methanesulfonic acid furan-2-ylmethyl ester and 0.83 g (6.00 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, filtered and is directly transferred to a reverse HPLC for purification (Zorbax stable bond C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:26]3[CH:27]=[CH:28][C:23]([CH2:22][C:21]([O:20][CH3:19])=[O:30])=[CH:24][CH:25]=3)=[CH:9][C:8]=2[C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:6][CH2:5]1)[CH3:2]
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)(C)C)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC1(c2ccc(C#Cc3ccc(CC(=O)OC)cc3)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112, 95.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 108.0 mg, 0.39 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 100.0 mg (72%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].[C:13]([O:17][C:18](=[O:23])[NH:19][CH2:20][CH2:21]Br)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18](=[O:23])[NH:19][CH2:20][CH2:21][N:3]1[C:2]([Br:1])=[C:6]([N+:7]([O-:9])=[O:8])[C:5]([Br:10])=[N:4]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1nc(Br)c([N+](=O)[O-])c1Br
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 14.7 %

Procedure:
A solution of 3,5-dibromo-4-nitropyrazole (2) (16.0 g, 59 mmol) in DMF (130 ml) was added dropwise over 20 min to a stirred solution of NaH (2.6 g, 65 mmol; 60% dispersion in oil washed beforehand with hexane under an inert atmosphere) in DMF (80 ml). After stirring for 10 min, a solution of (2-bromoethyl)carbamic acid tert-butyl ester (19.85 g, 88.5 mmol; obtained by reaction of 2-bromoethylamine with di(tert-butyl)dicarabonate) in DMF (35 ml) was added dropwise over 10 min. The reaction mixture was heated at 80° C. for 3 h and then the DMF was evaporated under reduced pressure. A mixture of DCM/water (200 ml, 1/1) was added to the residue and the organic phase was washed with water (100 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The [2-(3,5-dibromo-4-nitropyrazol-1-yl)ethyl]carbamic acid tert-butyl ester (3.6 g, 15%) was obtained in the form of a pale yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C.Br[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=1.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47]([NH:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])=[CH:42][CH:41]=1)#[CH:39]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:35]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([C:39]#[C:38][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])=[CH:44][CH:45]=2)=[CH:29][CH:30]=1)(=[O:37])[CH3:36]
Reactant: C#Cc1ccc(CC(=O)NNC(=O)OC(C)(C)C)cc1
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CC(=O)Nc1ccc(C#Cc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.2 %

Procedure:
Palladium (II) acetate (2.5 mg, 0.011 mmol) and triphenylphosphine (11 mg, 0.044 mmol) were added to diisopropylamine (4 ml), and the mixture was stirred at room temperature for 20 mins. N-(4-Bromophenyl)acetamide (78 mg, 0.365 mmol) and tert-butyl 2-[(4-ethynylphenyl)acetyl]hydrazinecarboxylate (100 mg, 0.365 mmol) were added, and the mixture was stirred at 70° C. for 2 hrs. Anhydrous acetonitrile (2 ml) was added, and the mixture was further stirred at 70° C. for 1 hr. The reaction mixture was cooled and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=97:3) to give tert-butyl 2-({4-[(4-acetamidophenyl)ethynyl]phenyl}acetyl)hydrazinecarboxylate (30 mg, yield 20%).
Reaction SMILES: [Cl:1][C:2]1[C@H:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH:7]=1.[Cl:9][C:10]([Cl:14])([Cl:13])[C:11]#[N:12]>>[Cl:9][C:10]([Cl:14])([Cl:13])[C:11](=[NH:12])[O:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH:7]=[C:2]1[Cl:1]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: O[C@@H]1CCCC=C1Cl
Product: N=C(O[C@@H]1CCCC=C1Cl)C(Cl)(Cl)Cl

Procedure:
In Scheme A step c, (R)-2-chloro-cyclohex-2-enylalcohol is contacted with trichloroacetonitrile to give (R)-2,2,2-trichloro-1-(2-chloro-cyclohex-2-enyloxy)-ethylideneamine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:33])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][C:12]=2[F:32])=[O:9])=[CH:4][CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:32][C:12]1[CH:13]=[C:14]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]2)[CH:15]=[CH:16][C:11]=1[N:10]([C:8]([C:5]1[CH:6]=[N:7][C:2]([O:41][C:38]2[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=2)=[CH:3][CH:4]=1)=[O:9])[CH3:33]
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)c(F)c2)CCN1C(=O)OC(C)(C)C
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)c(F)c2)CCN1C(=O)OC(C)(C)C
Temperature: 130 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-3-fluorophenyl}methyl)-2-methyl-1-piperazinecarboxylate (D68) and 4-fluorophenol using a method similar to that described for D55 in Description 55 although only 1 eq of 4-fluorophenol was added initially, the reaction was heated at 130° C. over-weekend, further 4-fluorophenol (2 eq) and potassium carbonate (4 eq) were added and the reaction was heated at 130° C. overnight. The product was purified by column chromatography. δH (CDCl3, 400 MHz) 8.07 (1H, s), 7.73 (1H, dd), 7.04 (7H, m), 6.74 (1H, d), 4.19 (1H, br.s), 3.80 (1H, d), 3.43 (4H, m), 3.33 (1H, d), 3.08 (1H, td), 2.67 (1H, d), 2.49 (1H, d), 2.13 (1H, dd), 2.00 (1H, m), 1.45 (9H, s), 1.21 (3H, d).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CC#N>[CH3:13][S:14]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:16])=[O:15]
Reactant: OCCCCl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)C(O)CCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 3-chloro-1-propanol (283 g, 2.99 mol) and triethylamine (629 mL, 4.5 mol) in CH3CN (3500 mL) at 10° C. was added dropwise methanesulfonyl chloride (518 g, 4.52 mol). The resulting reaction mixture was stirred overnight at room temperature, filtered and concentrated in vacuo to an oil. The oil was dissolved in CH2Cl2 and purified by filtration through silica gel. The appropriate fractions were combined and concentrated in vacuo to give the title compound 335 g (65%). TLC (Rf: 0.3; 20% EtOAc/Hexane). 1H NMR (CDCl3) δ2.1 (m, 2H, CH2), 2.96 (s, 3H, CH3) 3.59 (t, 2H, CH2), 4.28 (t, 2H, CH2). 13C NMR (CDCl3) δ31.5 (CH2), 37.0 (CH3), 40.2 (CH2), 66.3 (CH2).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Mg].C(=O)([O:17][CH2:18][CH3:19])OCC.Cl>C(OCC)C>[CH2:2]([C:18]([CH2:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[OH:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCOC(=O)OCC
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCCCCCC(O)(CCCCCCCCCC)CCCCCCCCCC
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Three moles of 1-bromodecane was slowly added to 3 moles of magnesium turnings in 0.6 liters of anhydrous ethyl ether (nitrogen atmosphere). One mole of diethyl carbonate in 0.151 anhydrous ethyl ether was slowly added to the mixture. After stirring for one hour at 30° C., the mixture was slowly poured into 1.8 liters of a cold 10% HCl solution. The organic layer was dried with magnesium sulfate and the ethyl ether evaporated off to give tri-n-decylcarbinol.
Reaction SMILES: [Cl:1]Cl.C(O)(=O)C.[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=3[CH:30]=2)=[CH:11][CH:10]=1>>[Cl:1][C:32]1[CH:31]=[C:12]([CH:11]=[CH:10][C:9]=1[O:8][CH3:7])[O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=2[CH:30]=1
Reactant: COc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Reactant: ClCl
Solvent: CC(=O)O
Product: COc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)C(C(F)(F)F)O3)cc1Cl
Yield: 53 %

Procedure:
To a stirred solution of chlorine in acetic acid (3.5 mL of 0.24 M solution, 0.84 mmol) was added 6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (0.31 g, 0.85 mmol) (Example 7). After 1 hour additional chlorine in acetic acid (1.5 mL of 0.24 M solution, 0.36 mmol) was added. After three additional hours additional chlorine in acetic acid (0.25 ml of 0.25 M solution, 0.06 mmol) was added. After 2.5 hours the reaction was quenched with aqueous 10% sodium bisulfite solution and the resulting mixture extracted with ethyl acetate. The organic phase was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo yielding a brown oil. The oil was dissolved in a minimum of hexanes which induced crystallization. Vacuum filtration of the mixture provided the title compound as yellow crystals (0.18 g, 53%): mp 205-207° C. 1H NMR (acetone-d6/300 MHz) 7.89 (s, 1H), 6.97-7.18 (m, 6H), 5.83 (q, 1H, J=7.0 Hz), 3.90 (s, 3H). FABLRMS m/z 400 (M+). FABHRMS m/z 399.0249 (M−H, Calc'd 399.0247). Anal. Calc'd for C18H12ClF3O5: C, 53.95; H, 3.02; Cl, 8.85. Found: C, 53.78; H, 3.08; Cl, 8.98.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].O[NH:29][C:30]([CH:32]1[CH2:34][CH2:33]1)=[NH:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:13]3[CH2:12][CH:11]([C:8]4[CH:7]=[CH:6][C:5]([C:2]([F:4])([F:1])[CH3:3])=[CH:10][CH:9]=4)[CH2:16][N:15]([C:17]([N:19]4[CH2:20][CH2:21][S:22][CH2:23][CH2:24]4)=[O:18])[CH2:14]3)[O:26][N:29]=2)[CH2:34][CH2:33]1
Reactant: N=C(NO)C1CC1
Reactant: CC(F)(F)c1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Product: CC(F)(F)c1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 150 mg (0.376 mmol) of the compound from Example 53A and 41.5 mg (0.414 mmol) of N-hydroxycyclopropanecarboximidamide were reacted Yield: 77.9 mg (44% of theory)
Reaction SMILES: [O:1]1[CH2:6]C[CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33](=[O:42])[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[S:31])=[CH:25][C:24]=3[F:43])[CH:14]=2)=[N:11][CH:12]=1.O1CCOC1C1C=CC(C2SC3C(=NC=CC=3OC3C=CC(N)=CC=3F)C=2)=NC=1>>[O:1]1[CH2:6][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33](=[O:42])[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[S:31])=[CH:25][C:24]=3[F:43])[CH:14]=2)=[N:11][CH:12]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Agent: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Yield: 60 %

Procedure:
Following the procedure described above for the synthesis of compound 32 (Scheme 9) but substituting compound 31 for compound 38, title compound 39 was obtained in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.49 (s, 1H), 12.48 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.56 (d, J=5.5 Hz. 1H), 8.42 (s, 1H), 8.33 (dd, J=8.2, 0.8 Hz, 1H), 8.07-8.03 (m, 1H), 7.99 (dd, J=8.2, 2.2 Hz, 1H), 7.56-7.55 (m, 2H), 7.38 (dd, J=8.7, 5.6 Hz, 2H), 7.19 (t, J=9.0 Hz, 2H), 6.70 (d, J=5.5 Hz, 1H), 5.90 (s, 1H), 4.12-4.06 (m, 2H), 4.04-3.98 (m, 2H), 3.84 (s, 2H). MS (m/z): 605.1 (M+H).