Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH3:49][CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([N:52]3[CH2:53][CH2:54][CH2:55][CH:50]([CH3:49])[CH2:51]3)=[O:24])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: CC1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCCN(C(=O)[C@@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.018 g) in DCM (0.5 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.018 g), HOBT (0.013 g) and triethylamine (0.039 ml) and the mixture was stirred at room temperature for 75 min. 3-Methylpiperidine(0.010 ml) was added and the resultant mixture stirred at room temperature for 48 h. The mixture was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The organic extract concentrated under reduced pressure and the residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 2:1, 1:1; ethyl acetate; ethyl acetate:methanol 2:1, 1:1) to give the title compound (0.007 g) as a white solid.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12](=[O:22])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].[NH2:23][CH2:24][CH2:25][NH:26][S:27]([C:30]1[C:31]2[CH:32]=[CH:33][N:34]=[CH:35][C:36]=2[CH:37]=[CH:38][CH:39]=1)(=[O:29])=[O:28]>>[C:13]([OH:28])(=[O:14])[C:12]([OH:11])=[O:22].[C:13]([OH:28])(=[O:14])[C:12]([OH:11])=[O:22].[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][NH:23][CH2:24][CH2:25][NH:26][S:27]([C:30]1[C:31]2[CH:32]=[CH:33][N:34]=[CH:35][C:36]=2[CH:37]=[CH:38][CH:39]=1)(=[O:29])=[O:28]
Reactant: COC(=O)COc1ccccc1Cl
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: CC(C)C[AlH]CC(C)C
Product: O=C(O)C(=O)O
Product: O=S(=O)(NCCNCCOc1ccccc1Cl)c1cccc2cnccc12
Yield: 65 %

Procedure:
By following the procedure as described in Example 1, DIBAL-H reduction of (2-chloro-phenoxy)-acetic acid methyl ester and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide (175 mg, 0.696 mmol) give 183 mg (0.451 mmol, 65% yield) of the free amine product as oil. The free amine is dissolved in EtOAc (10 mL) and treated dropwise with an EtOAc solution (10 mL) containing oxalic acid dihydrate (114 mg, 0.902 mmol) with stirring under nitrogen. The white suspension is stirred for 15 minutes, filtered and dried under vacuum at 60° C. to give 220 mg (0.375 mmol, 83% yield) of the title compound as a white powder. ESIMS: m/z 406 [(M+H)+, 35Cl], 408 [(M+H)+, 37Cl]. Analysis for C19H20ClN3O3S.1.8C2H2O4: calcd: C, 47.79; H, 4.19; N, 7.40; found: C, 47.70; H, 4.03; N, 7.45.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH3:23])[C:13]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:12]=3[S:11]2)=[CH:6][CH:5]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(O)(=O)C>[ClH:29].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:30](=[O:32])[CH3:31])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH3:23])[C:13]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:12]=3[S:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Agent: Cl
Solvent: CC(=O)O
Product: CCN(C)CCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21

Procedure:
A mixture of 0.9 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 5 ml of acetic anhydride and 5 ml of acetic acid is treated in the same manner as described in Example 6. The crude product thus obtained is recrystallized from a mixture of chloroform, ethanol and ether. 0.9 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride is thereby obtained as needles.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]2=[O:16])=[CH:5][CH:4]=1.C(N1C=[C:39]([CH2:41][C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)[N:38]=[CH:37]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO.C[C:53]#[N:54]>>[Cl:15][C:13]1[CH:12]=[CH:11][C:10](=[O:16])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:38]3[CH:37]=[CH:53][N:54]=[C:39]3[CH2:41][C:42]3[CH:43]=[CH:44][C:45]([C:46]#[N:47])=[CH:48][CH:49]=3)=[CH:4][CH:5]=2)[CH:14]=1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: O=c1ccc(Cl)cn1-c1ccc(CBr)cc1
Reactant: CC#N
Solvent: CO
Product: N#Cc1ccc(Cc2nccn2Cc2ccc(-n3cc(Cl)ccc3=O)cc2)cc1

Procedure:
The bromide from Step 2 (0.154 g, 0.516 mmol) and 4-(1-trityl-1H-imidazol-4-ylmethyl)-benzonitrile (0.22 g, 0.516 mmol) in CH3CN (2 mL) were heated at 55° C. After 18 hr methanol (3 mL) was added and the reaction was heated at reflux for 3 hrs, cooled and the solvent evaporated in vacuo. The residue was partitioned between sat. NaHCO3 and CH2Cl2 and extracted with CH2Cl2. The organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH2Cl2 5:95 as eluent) to afford the free base which was converted to the hydrochloride salt to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5](N)=[CH:4][C:3]1=2.[H+].[B-](F)(F)(F)[F:23]>>[CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([F:23])=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1cc2c(cc1N)C(C)(C)CCC2(C)C
Reactant: F[B-](F)(F)F
Agent: [H+]
Product: CCOC(=O)c1cc2c(cc1F)C(C)(C)CCC2(C)C

Procedure:
Reaction Schemes 1 and 2 provide examples for the synthesis of derivatives of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxylic acid, which are within the scope of Formula 2 and which are reacted with an amine of Formula 3 to provide (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene-2-yl)carbamoyl derivatives within the scope of Formula 1. Thus, as is shown in Reaction Scheme 1, ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxylate (Compound A) is nitrated to provide the corresponding 3-nitro compound (Compound B). The nitro group of Compound B is reduced to provide the corresponding 3-amino compound (Compound C) which is described in the publication Lehmann et al. Cancer Research, 1991, 51, 4804. Ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylate (Compound C) is brominated to yield the corresponding 4-bromo derivative (Compound D), which is converted by treatment with isoamylnitrite and reduction with H3PO2, to ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-bromonaphthalene-2-carboxylate (Compound E). Saponification of Compound E yields 5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-4-bromonaphthalene-2-carboxylic acid (Compound F) which is used as a reagent in accordance with Formula 2. Ethyl 5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylate (Compound C) is also diazotized and reacted with HBF4 to provide ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetra- methyl-3-fluoronaphthalene-2-carboxylate (Compound G) which serves either per se or after saponification as a reagent in accordance with Formula 2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[C:8](=O)[CH2:7]2)([OH:3])=[O:2].Cl.[NH2:18][OH:19]>C(O)C.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2=[N:18][OH:19])([OH:3])=[O:2]
Reactant: CC1(C)Oc2ccc(C(=O)O)cc2CC1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC1(C)CC(=NO)c2cc(C(=O)O)ccc2O1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
14.9 g of 6-carboxy-2,2-dimethyl-3-chromanone are dissolved in 100 ml of ethanol and 100 ml of pyridine, and after addition of 5.16 g of hydroxylamine hydrochloride the mixture is heated at 80° C. with stirring for 6 hours. The solvent is distilled off on a rotary evaporator. The residue is treated with water and adjusted to pH<1 using conc. hydrochloric acid, and the colorless crystals are filtered off.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH2:16]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15])[CH3:17]
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-fluorophenyl)-piperazine.
Reaction SMILES: [C@@H:1]12[CH2:8][N:7]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:6][C@@H:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[CH2:34]([O:41][CH2:42][C:43](Cl)=[O:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[F:26][C:10]1[CH:11]=[C:12]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:13]=[CH:14][C:9]=1[N:7]1[CH2:8][C@@H:1]2[C@@H:5]([CH2:4][N:3]([C:43](=[O:44])[CH2:42][O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:2]2)[CH2:6]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CNC[C@H]4C3)c(F)c2)C(=O)O1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)COCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
(S)-N-[[3-[4-[cis-3-(Carbobenzyloxy)-3,7-ciazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (150 mg, 0.30 mmol), methylene chloride (5 mL), and methanol (10 mL) are combined with 10% palladium on carbon (30 mg) and placed under a hydrogen atmosphere (balloon) for 15 hours. The reaction is filtered through celite and concentrated in vacuo to give crude (S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. The crude amine is taken up in methylene chloride (15 mL), cooled to 0° C., and triethylamine (0.09 mL, 0.67 mmol) and benzyloxyacetyl chloride (0.06 mL, 0.40 mmol) are added. The reaction is warmed to ambient temperature, stirred 15 hours, and diluted with methylene chloride (100 mL). The organic phase is washed with water (2×50 mL) and saline (150 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (95/5). The appropriate fractions are combined (Rf =0.41, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, mp 138-140° C.
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[CH2:57]([Mg]Br)[CH:58]([CH3:60])[CH3:59].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42]([OH:43])[CH2:57][CH:58]([CH3:60])[CH3:59])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C=O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CC(C)C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(O)CC(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.7 %

Procedure:
To a solution of 294 mg (0.377 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 16, in 5 ml of tetrahydrofuran, 0.5 ml (0.5 mmol) of 1.0 mol/L isobutylmagnesium bromide-tetrahydrofuran solution was added under an argon gas atmosphere, and the reaction solution was stirred at room temperature for 0.17 hour. Then, 1.0 ml (1.0 mmol) of 1.0 mol/L isobutylmagnesium bromide-tetrahydrofuran solution was further added thereto and the reaction solution was stirred at room temperature for 0.33 hour. After completion of the reaction, the reaction solution was poured into saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and then the solvent was distilled off under reduced pressure to provide 328 mg of the title compound as a foam (yield: quantitative).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([N:16]=[C:17]=[O:18])[CH2:14][CH3:15]>C(OCC)C>[CH2:13]([NH:16][C:17](=[O:18])[O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH3:15]
Reactant: CCCCCCCCCCCO
Reactant: CCCN=C=O
Solvent: CCOCC
Product: CCCCCCCCCCCOC(=O)NCCC
Yield: 89 %

Procedure:
For example, 8.6 g (50 mmol) of 1-undecanol, 5 ml (1.07 eq.) n-propyl isocyanate and 50 ml diethyl ether were heated in a stainless steel bomb at 65° for 72 hours. Solvent and excess isocyanate were removed on a rotary evaporator and the residue was crystallized from hexane to give 11.5 g (89%) of 1-undecyl propylcarbamate, mp 45°-45.5°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:22]([CH3:23])[C:6]2=[N:7][C:8]([O:11][C:12]3[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[C:13]=3[CH3:21])=[CH:9][CH:10]=[C:5]2[N:4]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:2]([O:1][CH2:2][C:3]1[N:22]([CH3:23])[C:6]2=[N:7][C:8]([O:11][C:12]3[CH:17]=[C:16]([CH3:18])[C:15]([O:19][C:8](=[O:11])[CH3:9])=[C:14]([CH3:20])[C:13]=3[CH3:21])=[CH:9][CH:10]=[C:5]2[N:4]=1)(=[O:1])[CH3:3]
Reactant: Cc1cc(Oc2ccc3nc(CO)n(C)c3n2)c(C)c(C)c1O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1nc2ccc(Oc3cc(C)c(OC(C)=O)c(C)c3C)nc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 163.9 %

Procedure:
To 400 ml of a solution of 38.0 g of 2-hydroxymethyl-5-(4-hydroxy-2,3,5-trimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine in pyridine, 69 ml of acetic anhydride were added dropwise under ice cooling. After stirring at room temperature for 3 hours, the reaction mixture was allowed to stand overnight at room temperature. The solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was separated and purified by chromatography through a silica gel column (eluting solvent n-hexane/ethyl acetate=1/2), whereby 39.5 g of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[Cl:21]C1C=C2C=CNC2=NC=1.N1C2C(=CC=CN=2)C=C1.[F:40][C:41]1[CH:42]=[C:43]([S:48](Cl)(=[O:50])=[O:49])[CH:44]=[C:45]([F:47])[CH:46]=1.S(Cl)(Cl)(=O)=O>>[Cl:21][C:17]1[CH:18]=[C:19]2[C:11]([C:9]([C:4]3[C:3]([F:20])=[C:2]([NH:1][S:48]([C:43]4[CH:42]=[C:41]([F:40])[CH:46]=[C:45]([F:47])[CH:44]=4)(=[O:49])=[O:50])[CH:7]=[CH:6][C:5]=3[F:8])=[O:10])=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncccc23)c1F
Reactant: Clc1cnc2[nH]ccc2c1
Agent: c1cnc2[nH]ccc2c1
Solvent: O=S(=O)(Cl)Cl
Product: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)cc(F)c2)c1F)c1c[nH]c2ncc(Cl)cc12

Procedure:
Additional compounds were prepared following the protocol of Scheme 67 Step 6, optionally substituting (3-Amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-1801 with (3-Amino-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl) -methanone P-2021 (prepared per Scheme 67 Steps 1-5, substituting 5-chloro-1H-pyrrolo[2,3-b]pyridine 80 with 1H-pyrrolo[2,3-b]pyridine 94 in Step 3) and/or 3,5-difluorobenzenesulfonyl chloride 610 with an appropriate sulfonyl chloride. The following compounds were prepared by this procedure:
Reaction SMILES: Cl[CH:2]([CH3:16])[C:3](=[O:15])[C:4](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[SH:17][CH2:18][CH2:19][OH:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:20][CH2:19][CH2:18][S:17][CH:2]([CH3:16])[C:3](=[O:15])[C:4](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: OCCS
Reactant: CCCON=C(C(=O)OCC)C(=O)C(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCON=C(C(=O)OCC)C(=O)C(C)SCCO
Temperature: 20 °C
Reaction time: 1.33 h
Yield: 85.1 %

Procedure:
Ethyl 4-chloro-3-oxo-2-n-propoxyiminovalerate (180.0 g.) was added to a stirred solution of 2-mercaptoethanol (71.6 g.) in chloroform (1.8 l.), and then a solution of triethylamine (93.1 g.) in chloroform (200 ml.) was added to the solution over 5 minutes. The solution was stirred at 20° C. for 80 minutes. After washing the resultant mixture with 10% hydrochloric acid twice, a saturated aqueous solution of sodium bicarbonate twice and water in turn, the solution was dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-(2-hydroxyethylthio)-3-oxo-2-n-propoxyiminovalerate (178.7 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH2:22]([S:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH2:22]([S:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:28])[CH3:23]
Reactant: CCSc1ncccc1C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCSc1ncccc1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 16.7 %

Procedure:
Preparation of example 66 from the title compound of Example 7 (hydrochloride) (30 mg, 0.096 mmol), 2-ethylsulfanyl-nicotinic acid (22 mg, 0.12 mmol), triethylamine (0.020 mL, 0.14 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (pre-rinsed silica with 3% triethylamine in ethyl acetate, eluted with 3% triethylamine in 19:6:1 ethyl acetate:hexane:methanol), also in an analogous manner, afforded the title compound (7 mg, 0.016 mmol) as a yellow powder in 17% yield.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[C:6]([O-:9])(=[O:8])[CH3:7].[NH4+:10].C(O)(=O)CC(O)=O>C(O)C>[NH2:10][CH:4]([CH:1]1[CH2:2][CH2:3]1)[CH2:7][C:6]([OH:9])=[O:8]
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Reactant: O=CC1CC1
Agent: O=C(O)CC(=O)O
Solvent: CCO
Product: NC(CC(=O)O)C1CC1
Temperature: 25 °C
Yield: 54 %

Procedure:
A mixture of cyclopropanecarboxaldehyde (150.2 g, 2.1 mol), ammonium acetate (329.9 g, 4.3 mol), malonic acid (223 g, 2.1 mol), and ethanol (850 mL) was stirred at reflux for 19 h. The reaction was analyzed by LCMS and determined to be complete. The mixture was allowed to cool to room temperature. The heterogeneous mixture was further cooled with an ice-bath and stirred 3 h prior to collecting the solid precipitate by suction filtration. The cake was washed with cold ethanol (displacement wash: 250 mL) and the solids dried under vacuum to provide 146.5 g of the desired compound (53% yield) as a white solid. mp: 206-208° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:27])([F:26])[C:8]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)([OH:13])[C:9]([F:12])([F:11])[F:10]>>[Cl:1][S:2]([C:18]1[CH:19]=[C:14]([C:8]([OH:13])([C:9]([F:12])([F:11])[F:10])[C:7]([F:6])([F:26])[F:27])[CH:15]=[CH:16][C:17]=1[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:5])=[O:3]
Reactant: COC(=O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1S(=O)(=O)Cl

Procedure:
To excess chlorosulfonic acid cooled with an ice-acetone bath can be added methyl 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoate with stirring. The solution should be stirred for several hours. Addition of the reaction mixture to ice and isolation of the product will give 2-chlorosulfonyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid, methyl ester. Reduction of 2-chlorosulfonyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid, methyl ester with zinc in acetic acid followed by isolation of the product will give 2-mercapto-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid, methyl ester.
Reaction SMILES: [CH2:1]([C:10]1[CH:46]=[CH:45][C:13]([C:14]([C:16]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[C:22]([C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:31][CH:30]=3)=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:10]1[CH:46]=[CH:45][C:13]([CH2:14][C:16]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[C:22]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:33][CH:34]=3)=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [H][H]
Reactant: CCCCCCCCCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCCCCCCCC)cc3)cc2C(=O)O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CCCCCCCCC)cc3)cc2C(=O)O)cc1

Procedure:
A mixture of 109 grams of 2,5-bis(4-nonylbenzoyl)terephthalic acid, 1500 mL of tetrahydrofuran, and 7.43 grams of 10% palladium on carbon (as a catalyst) was heated at 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The reaction mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2,5-bis(4-nonylbenzyl)terephthalic acid.