Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]O)[CH:28]=2)=[C:22]([CH3:35])[CH:21]=1)[CH3:15].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:1][C:2]3[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=3)[CH:28]=2)=[C:22]([CH3:35])[CH:21]=1)[CH3:15]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(/C=C/C(=O)OC)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
A solution of methyl (2E)-3-(4-hydroxyphenyl)acrylate (0.713 g, 4.00 mmol), [4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methanol (1.20 g, 4.00 mmol) and tributylphosphine (1.29 g, 6.40 mmol) in toluene (65 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (1.61 g, 6.40 mmol) was added in small portions, and the mixture was stirred at room temperature for 24 hr. Hexane (35 mL) was added to the reaction mixture. The precipitated insoluble material was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75), and recrystallized from ethyl acetate-hexane to give the title compound (1.58 g, yield 86%) as colorless crystals.
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)C.[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[CH2:23])[N:17]=1>CCCCCC.O1CCCC1>[CH:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:12]3[O:13][CH2:14][CH2:15][O:11]3)[N:17]=2)[CH2:1][CH2:23]1
Reactant: C=Cc1cccc(C2OCCO2)n1
Reactant: [Li]CCCC
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1cc(C2CC2)nc(C2OCCO2)c1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
5.60 ml of a 1.6 M solution of n-butyllithium in hexane are introduced dropwise into a suspension of 2.71 g of trimethylsulfonium iodide (13.3 mmol) in 25 ml of tetrahydrofuran cooled to -15° C. The solution is stirred at -15° C. for 20 minutes under nitrogen, and then a solution of 1.57 g of 2-[1,3]dioxolan-2-yl-6-vinylpyridine (8.90 mmol) in 5 ml of tetrahydrofuran is added dropwise. After stirring for 1 hour at -15° C., the suspension is stirred for 3 hours at room temperature. The tetrahydrofuran is evaporated off, the residue is taken up in water and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: hexane/ethyl acetate; 50:50). 1.24 g of a colorless oil are obtained.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([CH2:10][F:11])([CH2:8][F:9])[CH:6]=[CH2:7])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:9][CH2:8][C:5]([CH2:10][F:11])([CH:6]=[CH2:7])[C:4]([OH:12])=[O:3]
Reactant: C=CC(CF)(CF)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(CF)(CF)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 140.2 %

Procedure:
To a solution of 2,2-bis-hydroxymethyl-but-3-enoic acid ethyl ester (338 mg, 1.9 mmol) and 2,6-lutidine (813 mg, 0.88 mL, 7.6 mmol) in dichloromethane (10 mL) at −78° C. under nitrogen was added dropwise trifluoromethanesulfonic anhydride (1.07 g, 0.66 mL, 3.8 mmol) and the reaction mixture was warmed to room temperature and stirred at room temperature for 30 min. The solution was washed with ice-cold hydrochloric acid (1 M) and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude 2,2-bis-trifluoromethanesulfonyloxymethyl-but-3-enoic acid ethyl ester (1.9 mmol) as an orange oil which was used immediately in the next step. A solution of 2,2-bis-trifluoromethanesulfonyloxymethyl-but-3-enoic acid ethyl ester (1.9 mmol) in tetrahydrofuran (5 mL) was stirred at 0° C. under nitrogen. Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 4.75 mL, 4.75 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. The solvent was evaporated. The residue was dissolved in dichloromethane and the solution was washed with saturated sodium hydrogen carbonate solution, water and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 19:1 to 4:1 to afford 2,2-bis-fluoromethyl-but-3-enoic acid ethyl ester (1.9 mmol) contaminated with solvent as a clear oil. A solution of crude 2,2-bis-fluoromethyl-but-3-enoic acid ethyl ester (1.9 mmol) in tetrahydrofuran (10 mL) was stirred at 0° C. under nitrogen. A solution of lithium hydroxide monohydrate (240 mg, 5.7 mmol) in water (2.5 mL) was added and the reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 24 h. The reaction mixture was acidified to pH 2 with hydrochloric acid (2 M). Water was added and the mixture was extracted with diethyl ether. The organic extracts were combined, washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford the title compound (400 mg) as a clear oil. 1H NMR (300 MHz, d6-DMSO) δ 4.54-4.83 (m, 4H), 5.33 (d, J=17.8 Hz, 1H), 5.36 (d, J=10.7 Hz, 1H), 5.81 (dd, J=17.8, 10.7 Hz, 1H), 13.0-13.5 (br s, 1H). LCMS (m/z) 149.2 [M−H], Tr=1.45 min.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
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: F[B-](F)(F)F
Reactant: CCOC(=O)c1cc2c(cc1N)C(C)(C)CCC2(C)C
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-tetramethyl-3-fluoronaphthalene-2-carboxylate (Compound G) which serves either per se or after saponification as a reagent in accordance with Formula 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:19])[CH2:11][C:12](OC(C)(C)C)=O)[CH:5]=1.CI.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:19])[CH2:11][CH3:12])[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCC(=O)c1cccc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a stirred solution of 3-tert-butoxycarbonylacetyl-benzoic acid methyl ester (11.1 g) and MeI (2.2 mL) in DMF (40 mL) was added portionwise at 0° C. NaH (55% dispersion in mineral oil, 1.4 g). Stirring was continued at 0° C. for 15 min and at 20° C. for 30 min. The mixture was partitioned between AcOEt and brine, the pH being set to 7 by the addition of 3N HCl. The organic layer was dried and evaporated. The residue was stirred in a mixture of CH2Cl2 (30 mL) and TFA (30 mL) for 40 min at 20° C. After the evaporation of the solvents, the solution of the residue in AcOEt was extracted with ice-cold sat. Na2CO3 solution and the aqueous extracts were immediately acidified with 3N HCl and extracted with AcOEt. The solvent of this extract was evaporated and the residue heated in a mixture of toluene (40 mL) and 3N HCl (3 mL) to 100° C. for 1 h. The cooled mixture was diluted with AcOEt, washed with sat. NaHCO3 and brine, dried and evaporated to give 3-propionyl-benzoic acid methyl ester (3.87 g) as white solid, MS (ISP) 193.2 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].O=C1CCC(=O)N1[O:17][C:18](=O)[CH:19]([NH:27][C:28]([O:30][CH2:31][CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:20][S:21][S:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C([O-])(O)=O.[Na+].C1COCC1.CO.C(Cl)Cl>[C:23]([S:22][S:21][CH2:20][CH:19]([NH:27][C:28]([O:30][CH2:31][CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:17])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)SSCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Reactant: NCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)SSCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-Aminohexanoic acid (0.158 g, 1.2 mmole) dissolved in 0.1M NaHCO3 (2.0 mL) was added the NHS ester 2 (0.68 g, 1.3 mmole) in 4 mL of anhydrous THF. The reaction mixture was stirred at RT for 2 hr. The solvent was completely evaporated and the dried solid residue obtained was dissolved in CH3OH/CH2Cl2 mixture and purified by silica gel column chromatography using 10% CH3OH/CH2Cl2 and obtained 3 as a white solid on evaporation the solvent. Yield: 0.5 g (77%).
Reaction SMILES: Br.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:21][CH2:20]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1Br.[CH3:23][C:24]1([CH3:44])[C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[C:27](=[O:43])[NH:26][CH2:25]1>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:21][CH2:20]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:43])[NH:26][CH2:25][C:24]2([CH3:44])[CH3:23]
Reactant: CC1(C)CNC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cc1Br
Agent: Br
Product: CC1(C)CNC(=O)c2ccc(-c3cc(-c4ccc(S(=O)(=O)NC5CC5)cc4)cnc3N)cc21
Yield: 37.2 %

Procedure:
General method C was applied to 4-(6-amino-5-bromopyridin-3-yl)-N-cyclopropylbenzenesulfonamide hydrobromide (92 mg, 0.25 mmol) and 4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (75 mg, 0.25 mmol) to give 4-(6-amino-5-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)-N-cyclopropylbenzenesulfonamide (43 mg, 37% yield) as a white solid after purification by flash chromatography over silica gel (2-5% MeOH/DCM eluent). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.06 (d, J=8.5 Hz, 2H), 7.96-8.02 (m, 2H), 7.80 (d, J=1.5 Hz, 1H), 7.75 (dd, J=7.5, 1.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 6.00 (s, 2H), 3.20 (d, J=2.0 Hz, 2H), 2.06-2.18 (m, 1H), 1.33 (s, 6H), 0.33-0.55 (m, 4H); MS (EI) m/z=463.6 [M+1]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([Cl:24])[C:9]2[O:13][C:12]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)O)=[CH:11][C:10]=2[CH:23]=1>C1CCCCC1>[Cl:5][C:6]1[CH:7]=[C:8]([Cl:24])[C:9]2[O:13][C:12]([CH:14]([Cl:3])[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:11][C:10]=2[CH:23]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(Cl)cc1)c1cc2cc(Cl)cc(Cl)c2o1
Solvent: C1CCCCC1
Product: Clc1ccc(C(Cl)c2cc3cc(Cl)cc(Cl)c3o2)cc1

Procedure:
To 0.35 mole of thionylchloride in 300 ml of cyclohexane, 0.31 mole of (5,7-dichlorobenzofuran-2-yl)(p-chlorophenyl)carbinol are portions-like added followed by 3-hour agitation at ambient temperature; then the solution is concentrated, filtered out and crystallized from cyclohexane: m.p. 72°-74° C.
Reaction SMILES: CN(C)CCNC.BrC1OC(C=O)=CC=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][C:36]#[N:37]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[C:35](=[CH:28]/[C:26]2[O:27][C:23]([N:20]([CH2:21][CH2:22][N:17]([CH3:16])[CH3:18])[CH3:19])=[CH:24][CH:25]=2)/[C:36]#[N:37])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CN1CCN(c2ccc(C=O)o2)CC1
Agent: CNCCN(C)C
Agent: O=Cc1ccc(Br)o1
Product: COc1ccc(/C(C#N)=C/c2ccc(N(C)CCN(C)C)o2)cc1OC
Yield: 96.9 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from N,N,N′-trimethylethylenediamine (3.06 g) was introduced into 5-bromo-2-furaldehyde (1.75 g), to thereby yield 5-(4-methyl-piperazin-1-yl)-furan-2-carbaldehyde (yield: 1.18 g, 60%). The produced 5-(4-methyl-piperazin-1-yl)-furan-2-carbaldehyde (1.18 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.06 g) through Method A (production step 2), to thereby yield the target product (yield: 2.06 g, 96%).
Reaction SMILES: CC(C)(C)[Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:27][CH2:28][CH2:29][S:30][S:31][CH2:32][CH2:33][NH:34][C:35](=[O:74])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][Si](C1C=CC=CC=1)(C1C=CC=CC=1)C(C)(C)C)=[O:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][C:35]([NH:34][CH2:33][CH2:32][S:31][S:30][CH2:29][CH2:28][NH:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][OH:4])=[O:74]
Reactant: CC(C)(C)[Si](OCCOCCOCCOCCCCCCCCCCCC(=O)NCCSSCCNC(=O)CCCCCCCCCCCOCCOCCOCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(CCCCCCCCCCCOCCOCCOCCO)NCCSSCCNC(=O)CCCCCCCCCCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 30 (1.76 g, 1.40 mmol) was dissolved in tetrahydrofuran (50 mL) and terabutylammonium fluoride in tetrahydrofuran (1.0 M, 2.95 mL) was added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo. The resulting oil was dissolved in dichloromethane (200 mL) and the solution was washed with aqueous hydrochloric acid (1 N, 100 mL), water (75 mL) and brine (75 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([CH:4]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[C:5]([OH:7])=[O:6])([CH3:3])=[CH2:2].C(=O)([O-])[O-].[K+].[K+].[C:19]1(C)C=CC=C[CH:20]=1.S(OCC)(OCC)(=O)=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([CH:4]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:19][CH3:20])=[O:6])([CH3:3])=[CH2:2]
Reactant: C=C(C)C(CC=C(C)C)C(=O)O
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Solvent: O
Product: C=C(C)C(CC=C(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 82.9 %

Procedure:
In a nitrogen atmosphere, a mixture of 200.01 g of 2-isopropenyl-5-methyl-4-hexenoic acid (1) having a purity of 85.4%, 89.82 g of potassium carbonate, 11.28 g of tetrabutylammonium chloride, and 800 g of toluene was heated to from 95° C. to 100° C., while being stirred, and then 191.8 g of diethyl sulfate was added dropwise thereto over 35 minutes. The reaction mixture was heated continuously for 2 hours, then cooled to room temperature, and subjected to addition of 510 g of water. The toluene solution was separated from the resulting mixture and then subjected to typical work-up including washing, drying and concentration to obtain the crude product. The crude product was distilled under reduced pressure to obtain 193.4 g of the intended product having a purity of 99.7%. The yield was 97%.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:26][CH:25]3[CH2:24][C:23](=[O:27])[CH2:22][CH2:21]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.[BH4-].[Na+]>COCCOC>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:26][CH:25]3[CH2:24][CH:23]([OH:27])[CH2:22][CH2:21]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCC(=O)CC2C3)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCC(O)CC2C3)cc1F
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((4-oxobicyclo[4.1.0]heptan-1-yl)methoxy)benzoate (0.63 g, 1.70 mmol) was dissolved in 1,2- dimethoxyethane (5 mL), sodium borohydride (0.13 g, 3.40 mmol) was added. The reaction mixture was stirred for 0.5 hour and quenched with slow addition of water (5 mL) followed by ethyl acetate (10 mL). To this reaction mixture was added concentrated hydrochloride (37%, 1.0 mL) and stirred for 10 minutes. The organic layer was separated and the solvent was concentrated in vacuo to afford the title compound as a solid (0.13 g, 19%): 1H NMR (300 MHz, CDCl3) (7.36 (d, J=8.5 Hz, 1H), 6.40 (d, J=12.7 Hz, 1H), 3.78 (d, J=9.2 Hz, 1H), 3.62 (d, J=9.4 Hz, 1H), 2.40-2.30 (m, 4H), 2.20-2.07 (m, 2H), 1.99-1.92 (m, 1H), 1.53 (s, 9H), 1.42-1.33 (m, 1H), 1.29-1.09 (m, 2H), 0.89-0.82 (m, 4H), 0.76-0.71 (m, 1H, 0.65-0.60 (m, 2H), 0.47 (t, J=5.3 Hz, 1H); MS (ES+) m/z 377.2 (M+1).
Reaction SMILES: Cl[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][O-].[K+].S(=O)(=O)(O)O.[NH2:16][C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][N:18]=1>C(O)C>[OH:23][C:21]1[CH:20]=[CH:19][N:18]2[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:16]=[C:17]2[CH:22]=1
Reactant: CCOC(=O)C(Cl)=C[O-]
Reactant: Nc1cc(O)ccn1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(O)ccn12
Temperature: 25 °C
Yield: 14.9 %

Procedure:
To a chilled (0° C.) solution of potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (16.4 g, 86.3 mmol) in concentrated sulfuric acid (43.5 mmol) and ethanol (50 mL) was added 2-aminopyridin-4-ol (3 g, 27 mmol). The resulting mixture was warmed to ambient temperature and refluxed for 10 hours. The reaction was concentrated and suspended in EtOAc. The solids were isolated to afford 829 mg of pure product. The supernatant was concentrated, and subjected to chromatography on silica with 30% EtOAc/Hexanes as eluent to afford a second batch of desired product (5.8 g, 80% purity) as a brown, viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18]O)[CH3:16])[C:9]=2[C:8](=[O:32])[N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:6]1=[O:39].[OH:45][CH2:46][CH2:47][C:48]1[NH:49][CH:50]=[CH:51][N:52]=1>>[F:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:24][CH:25]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18][N:49]3[CH:50]=[CH:51][N:52]=[C:48]3[CH2:47][CH2:46][OH:45])[CH3:16])[C:9]=2[C:8](=[O:32])[N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:6]1=[O:39]
Reactant: CCNC(=O)Nc1ccc(-c2sc3c(c2CN(C)CCO)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Reactant: OCCc1ncc[nH]1
Product: CCNC(=O)Nc1ccc(-c2sc3c(c2CN(C)CCn2ccnc2CCO)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 14.8 %

Procedure:
The similar reaction to that of Example 120 was performed using N-(4-(1-(2,6-difluorobenzyl)-5-(((2-hydroxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-ethylurea (135 mg, 0.218 mmol) and 2-(2-hydroxyethyl)imidazole (122 mg, 1.09 mmol) to give the title compound (23 mg, 15%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OC[C:35](C)(C)[C:36]([NH:38]C)=O>>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:38][CH2:36][CH3:35])=[O:9]
Reactant: CNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Product: CCNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC

Procedure:
From 3-[2,3-Dimethoxy-6-(1-oxo-indan-4-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 199) and 2-Methylamine solution following the procedure for the preparation of Compound 200. Purification by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=1.C(O)=O>C(O)(C)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: Fc1cccc(C2=CCNCC2)c1F
Agent: [Pd]
Solvent: O=CO
Solvent: CC(C)O
Product: Fc1cccc(C2CCNCC2)c1F
Reaction time: 6 h

Procedure:
A mixture of 4-(2,3-difluorophenyl)-1,2,3,6-tetrahydropyridine (2.4 g, 12.3 mmol), palladium on active carbon (0.5 g) and formic acid (2.4 ml) in isopropanol (50 ml) was hydrogenated at 50 psi for 6 h under hydrogen gas. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness. Aqueous sodium carbonate (10%, 50 ml) was added. The aqueous phase was extracted with ethylacetate (3×60 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness. Yield: 2.11 g. MS m/z (rel. intensity, 70 eV) 197 (M+, bp), 196 (53), 140 (11), 127 (10), 114 (6).