Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][O:23][C:24](=[O:29])[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:3]=1)([CH3:27])[CH3:26]
Reactant: CC1(C)Cc2cc(C#N)ccc2NC1c1cccc(N)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C#N)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 57.6 %

Procedure:
A mixture of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (0.64 g, 2.3 mmol), 2-bromo-2-methyl-propionic acid methyl ester (1.25 g, 6.9 mmol) and potassium carbonate (1.59 g, 11.5 mmol) in N,N-dimethylformamide (6 mL) was stirred at 25° C. for 5 d. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(30% ethyl acetate/hexanes) to afford 2-[3-(6-cyano-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (500 mg, 43%) as a brown oil: LC/MS m/e calcd for C23H27N3O2 (M+H)+: 378.49, observed: 378.2.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([C@:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:5]1[O:6][C:7]2[C:13]([C@:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCC[C@@](O)(c1cccc2cc(C(C)(C)C)oc12)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1cccc2cc(C(C)(C)C)oc12)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
(R)-tert-butyl 3-((S)-1-(2-tert-butylbenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (250 mg, 0.53 mmol) was dissolved in 20% TFA/CH2Cl2 (4 mL). The reaction mixture was stirred at rt for 1 h. The mixture was quenched with satd aq NaHCO3 (15 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4. The filtrate was evaporated to give a residue, which was purified by preparative HPLC to afford pure (S)-1-(2-tert-butylbenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (185 mg, 94%). 1H NMR (CDCl3): 0.95 (s, 1), 1.24 (m, 2H), 1.36 (s, 9H), 1.49 (m, 3H), 1.64 (m, 2H), 2.02 (m, 2H), 2.55 (m, 2H), 2.82 (s, 1H), 3.1 (s, 1H), 3.25 (m, 5H), 3.66 (m, 1H), 6.35 (s, 1H), 7.18 (t, 1H), 7.28 (d, 1H), 7.42 (d, 1H), 8.96 (s, 1H), 9.33 (s, 1H)
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].[O:27]=[S:28]1(=[O:42])[C:33]2=[CH:34][CH:35]=[CH:36][C:37]3=[CH:38][CH:39]=[CH:40][C:31](=[C:32]23)[C:30](=[O:41])[NH:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:29]3[C:30](=[O:41])[C:31]4[CH:40]=[CH:39][CH:38]=[C:37]5[CH:36]=[CH:35][CH:34]=[C:33]([C:32]=45)[S:28]3(=[O:42])=[O:27])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C1NS(=O)(=O)c2cccc3cccc1c23
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3C(=O)c4cccc5cccc(c45)S3(=O)=O)[C@H](C)[C@H]12
Yield: 58.2 %

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (64.8 mg, 0.174 mmol), 1,1-dioxo-2,3-dihydro-naphtho[1,8de][1,2]thiazin-3-one (34.5 mg, 0.145 mmol), and triphenylphosphine (46 mg, 0.174 mmol) in anhydrous tetrahydrofuran (2 mL) was cooled in an ice bath and stirred under a nitrogen atmosphere. Diisopropyl azodicarboxylate (0.034 mL, 0.174 mmol) was added and the resulting mixture was stirred at 0-5° C for 10 minutes. The mixture was concentrated under vacuum and the residue was purified by preparative layer chromatography on a 1 mm×20 cm×20 cm silica gel GF plate using 7:3 ethyl acetate-hexanes as the developing solvent. The product band was removed and eluted with ethyl acetate to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-1-methyl-2-(1,1,3-trioxo-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-2-ylmethyl)-carbapen-2-em-3-carboxylate (49 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:9][C:7](=[O:8])[CH:6]([C:10]([CH3:12])=[O:11])[C:4](=[O:5])[CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O.N1CCCCC1>C1C=CC=CC=1>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[CH:12][C:10]([CH:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:9][C:7]1=[O:8])=[O:11]
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Reactant: O=Cc1cccs1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC1=CC(=O)C(C(=O)C=Cc2cccs2)C(=O)O1
Temperature: 50 °C
Reaction time: 7 h
Yield: 57.2 %

Procedure:
To a solution of 65.0 g (0.39 mole) of dehydroacetic acid and 47.0 g (0.42 mole) of thiophene-2-aldehyde in 370 ml of benzene was added dropwise 6.8 g of piperidine with cooling in an ice-water bath. After termination of the dropwise addition, the mixture was stirred at 50° C. for 7 hours. After the reaction, the solvent was concentrated under a reduced pressure. The precipitated crystal was collected by filtration and recrystallized from toluene to obtain 58.5 g (yield: 58%) of 3-(2-thienylacryloyl)-6-methyl-2H-pyran-2,4(3H)-dione in the form of a light crystal, m.p. 162°-164° C.
Reaction SMILES: [C:1]([C:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:11]([N:13]=[C:14]=[S:15])[CH3:12]>O1CCCC1>[CH2:11]([NH:13][C:14]([N:8]1[CH2:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]1)=[S:15])[CH3:12]
Reactant: CC(C)(C)C1=CCNCC1
Reactant: CCN=C=S
Solvent: C1CCOC1
Product: CCNC(=S)N1CC=C(C(C)(C)C)CC1

Procedure:
In 20 ml. of anhydrous tetrahydrofuran there is dissolved 5.0 grams of 4-t-butyl-1,2,3,6-tetrahydropyridine. Stirring is initiated and there is added 3.14 grams of ethylisothiocyanate in 10 ml. of anhydrous tetrahydrofuran allowing the reaction to run at room temperature. After stirring the reaction mixture for 18 hours, the tetrahydrofuran is evaporated in vacuo to give N-ethyl-4-t-butyl-1,2,3,6-tetrahydro-1-pyridinethiocarboxamide.
Reaction SMILES: C([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][C@@H:13](O)[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=O)C.CC1C([C@@H]2SC[C@@H]3CN(C(OC(C)(C)C)=O)CCN3C2)=CC=C2C=1COC2=O>>[CH3:24][C:15]1[C:14]([C@H:13]2[S:4][CH2:5][C@@H:6]3[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:9][CH2:10][N:11]3[CH2:12]2)=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][O:18][C:19]2=[O:23]
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[C@@H](O)c1ccc2c(c1C)COC2=O
Agent: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CS2)ccc2c1COC2=O
Product: Cc1c([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CS2)ccc2c1COC2=O

Procedure:
Synthesis from (S)-tert-butyl 3-(acetylthiomethyl)-4-((S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazine-1-carboxylate is analagous to that for the synthesis of (3S,9aS)-tert-butyl 3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)hexahydropyrazino[2,1-c][1,4]thiazine-8(1H)-carboxylate: 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 5.28 (s, 2H), 4.41 (dd, J=2.2, 10.9 Hz, 1H), 4.04 (bm, 2H), 2.93-3.15 (m, 2H), 2.53-2.88 (m, 5H), 2.33-2.45 (m, 5H), 1.51 (s, 9H); LC/MS: [(M+1)]+=405.2.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([NH:14][CH2:15][CH2:16][NH2:17])[CH3:13]>N1C=CC=CC=1>[CH2:12]([NH:14][CH2:15][CH2:16][NH:17][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNCCN
Solvent: c1ccncc1
Product: CCNCCNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
A solution of 95 grams of p-toluenesulfonyl chloride in 175 ml. of pyridine was added dropwise to a stirred solution of 135 grams of N-ethyl ethylenediamine in 250 ml. of pyridine cooled in an ice bath. After addition was completed, the mixture was stirred one-half hour at room temperature then heated in a steam bath for one-half hour. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with sodium carbonate solution and water. After drying the ethyl acetate portion over magnesium sulfate, the solvent was removed in vacuo to obtain N-[2-(ethylamino)ethyl]-p-toluenesulfonamide as a viscous oil which crystallized on standing. Analytical sample prepared from ether-hexane melted at 50°-53°C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([NH:18]C(=O)OC(C)(C)C)[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[C:7]([O:26][CH3:27])[CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>>[Cl:1][C:2]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[C:7]([O:26][CH3:27])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(-c3cccc(NC(=O)OC(C)(C)C)c3)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(Cl)nc(-c3cccc(N)c3)c2cc1OC
Temperature: 5 °C
Yield: 96.9 %

Procedure:
Under a nitrogen atmosphere, 420 mg (1.00 mmol) of t-butyl [3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenyl]carbamate was allowed to cool down to 5° C., trifluoroacetic acid (1 mL) was added dropwise while stirring, and the mixture was stirred at room temperature. The mixture was stirred for 1.25 hours, then allowed to cool down to 5° C. to 10° C., 2 N aqueous sodium hydroxide solution (6.2 mL) was added dropwise to precipitate pale yellow crystals. The mixture was stirred at room temperature for 15 minutes, and the precipitated crystals were filtration and dried to give 306 mg of a target product (yield: 95.6%).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)(Cl)Cl.[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[Br:26][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: BrBr
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 300 mL three-neck flask, 5.8 g (23 mmol) of 9-phenylanthracene and 100 mL of carbon tetrachloride were placed. Then, 30 mL of a carbon tetrachloride solution containing 4.0 g (25 mmol) of bromine was dripped into the mixture under nitrogen stream. After dripping, the solution was stirred for 12 hours at room temperature. After a certain period, 100 mL of a 1.0 M sodium thiosulfate solution was added and stirred for 1 hour, and an aqueous layer of the mixture was extracted with chloroform. The obtained extracted solution and the organic layer were combined and washed with a 0.10 M sodium thiosulfate solution, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline in this order, and then, the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a solid. A toluene solution of the solid was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was condensed to give a solid. Methanol was added to the solid, and this suspension was irradiated with ultrasonic waves. Then, 6.4 g of a solid substance, which was target pale yellow powder, was obtained by suction filtration in a yield of 84%.
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1.[CH2:38]([O:45][C:46]1[C:47]([C:69]([N:71]([CH2:75][CH2:76]O)[CH:72]([CH3:74])[CH3:73])=[O:70])=[N:48][C:49]([CH2:53][C:54]2([C:59]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[CH:62]=[CH:61][CH:60]=3)[CH2:58][CH2:57][CH2:56][CH2:55]2)=[N:50][C:51]=1[OH:52])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][C:46]1[C:51](=[O:52])[N:50]=[C:49]([CH2:53][C:54]2([C:59]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[CH:62]=[CH:61][CH:60]=3)[CH2:55][CH2:56][CH2:57][CH2:58]2)[N:48]2[CH2:76][CH2:75][N:71]([CH:72]([CH3:73])[CH3:74])[C:69](=[O:70])[C:47]=12)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN1CCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O

Procedure:
This compound was prepared following the same method as described for pure 9-Benzyloxy-2-methyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (352) from 5-(benzyloxy)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropyl-2-((1-(naphthalen-1-yl)cyclopentyl)methyl)pyrimidine-4-carboxamide (511).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:19]=[CH:18][C:17]([CH3:21])([CH3:20])[C:16]2[C:9]=1[CH:10]=[C:11]1[C:15]=2[CH:14]=[N:13][N:12]1[CH2:22][C@H:23](O)[CH3:24].C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:33]([C@@H:23]([CH3:24])[CH2:22][N:12]1[C:11]2=[CH:10][C:9]3[C:16]([C:17]([CH3:21])([CH3:20])[CH:18]=[CH:19][C:8]=3[O:7][CH3:6])=[C:15]2[CH:14]=[N:13]1)=[N+:34]=[N-:35]
Reactant: COC1=C2C=c3c(cnn3C[C@@H](C)O)=C2C(C)(C)C=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2C(C)(C)C=C1
Yield: 89.2 %

Procedure:
0.8 ml (10.2 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.41 g (5.2 mmol) of (R)-1-(7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 2.9 ml (20.4 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time arid the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.76 g (11.4 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.38 g (89%) of (S)-1-(2-azido-propyl)-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[F:13][C:10]([F:11])([F:12])[C:9]1[C:4]([CH:1]([OH:3])[CH3:2])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1ncccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ncccc1C(F)(F)F
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
Dissolve 2-acetyl-3-trifluoromethylpyridine (76 g, 0.4021 moles) in anhydrous MeOH (1100 mL) and cool the resulting solution at −10° C. under N2 atmosphere. Add NaBH4 (16.0 g, 0.4238 moles) in small portions over a period of 45 minutes and stir further at −10° C. for an additional 45 minutes. Quench the reaction mixture with water (100 mL) and warm to room temperature. Concentrate the reaction mixture under vacuum, dilute with water (500 mL), extract with EtOAc (3×250 mL) and dry (MgSO4). Filter and concentrate the dried extract under vacuum to afford the title product as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([Cl:19])[C:13]([C:20]([OH:22])=O)=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].[CH:24]([N:27]1[C:40]2[C:39](=[O:41])[CH2:38][C:32]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH2:31][C:30]=2[CH:29]=[N:28]1)([CH3:26])[CH3:25]>>[Cl:19][C:14]1[C:13]([C:20]([N:35]2[CH2:34][CH2:33][C:32]3([CH2:38][C:39](=[O:41])[C:40]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:28]=[CH:29][C:30]=4[CH2:31]3)[CH2:37][CH2:36]2)=[O:22])=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:23])[CH:10]=2)[N:15]=1
Reactant: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C(=O)O)cc2c1
Reactant: CC(C)n1ncc2c1C(=O)CC1(CCNCC1)C2
Product: CC(C)n1ncc2c1C(=O)CC1(CCN(C(=O)c3cc4cc(OCC(=O)OC(C)(C)C)ccc4nc3Cl)CC1)C2

Procedure:
6-(2-tert-butoxy-2-oxoethoxy)-2-chloroquinoline-3-carboxylic acid and 1-isopropyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(1H)-one were coupled by a method analogous to that described for Example 1 to give tert-butyl 2-(2-chloro-3-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-ylcarbonyl)quinolin-6-yloxy)acetate. This material (30 mg, 0.053 mmol) was suspended in ammonia (2 mL, 10 mmol, 7 M in methanol) and stirred at room temperature for 18 hours. The reaction was concentrated to give the title compound (27 mg, 100%). +ESI (M+H) 510.4.
Reaction SMILES: I.[PH2](O)=O.C(OC(=O)C)(=O)C.[CH3:12][C:13]1[NH:14][CH:15]=[C:16]([CH3:21])[C:17]=1[C:18](=[O:20])[CH3:19].[OH-].[NH4+].[CH3:24][C:25]([CH3:27])=O>O>[CH3:12][C:13]1[NH:14][C:15]([CH:25]([CH3:27])[CH3:24])=[C:16]([CH3:21])[C:17]=1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC(C)=O
Agent: I
Agent: O=[PH2]O
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1c(C)[nH]c(C(C)C)c1C
Reaction time: 0.5 h

Procedure:
Aqueous hydriodic acid (10 ml) and 2 ml of 50% hypophosphorous acid were cooled and stirred while 10 ml of acetic anhydride was slowly added. 2,4-Dimethyl-3-acetyl-pyrrole (548 mg) was dissolved in the solution, 0.6 ml of acetone added, and the mixture was stirred for 1/2 hr. by which time a yellow precipitate had formed and redissolved and the solution had turned yellow; the final temperature was 37° C. It was poured into 100 ml of water and 30 ml of ammonium hydroxide kept at 20° C. The nearly colourless product separated as plates (662 mg, 92%). At 138° C. these changed to cubes which either melted at 165° C. or turned to irregular needles, m.p. 171°-173° C. For analysis, it was recrystallized from aqueous ethanol as colourless plates, m.p. 165.5° C. or 171.5°-173° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[CH2:26]([N:22]([CH2:23][CH2:24][OH:25])[C:3]1[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1)[CH3:27]
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br
Reactant: OB(O)c1cncnc1
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 195.1) and pyrimidin-5-ylboronic acid to afford an off-white foam. HPLC (Condition 4) tR=5.43 min, UPLC-MS (Condition 3) tR=1.05 min, m/z=464.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=6.84 Hz, 3H) 3.14 (m, J=7.00, 7.00, 7.00 Hz, 2H) 3.32-3.52 (m, 4H) 4.61 (t, J=5.08 Hz, 1H) 7.69 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.60 Hz, 2H) 8.10 (d, J=2.35 Hz, 1H) 8.77 (d, J=1.95 Hz, 1H) 9.01 (s, 2H) 9.19 (s, 1H) 10.35 (s, 1H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[Cl:6][C:7]1[CH:8]=[C:9](O)[CH:10]=[C:11]([C:13]([N:15]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16][CH:17]=[CH2:18])=[O:14])[CH:12]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([N:15]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:16][CH:17]=[CH2:18])=[O:14])[CH:10]=[C:9]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[CH:8]=1
Reactant: OCCCO
Reactant: C=CCN(C(=O)c1cc(O)cc(Cl)c1)C1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCCO)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of tetrahydrofuran (100 mL), 1,3-propanediol (1.6 mL, 30 mmol) and phenol 16 (4.3 g, 15 mmol) at 0° C., was added diethyl azodicarboxylate (DEAD, 3.6 mL, 23 mmol) dropwise over 10 min. The solution was warmed to ambient temperature and stirred for 16 h, prior to concentration in vaciio. The oil was partially purified by chromatography on silica gel to provide alcohol 17 (3.9 g) contaminated with Mitsunobu by-products. This material was used directly in subsequent experiments. 1H NMR (300 MHz, CDCl3) δ 6.93 (s, 2H), 6.8 (s, 1H), 5.9 (bs, 1H), 5.18 (d, 2H), 4.4-3.8 (m, 7H), 2.05 (m, 2H), 1.4-1.9 (m, 10H). Mass spectrum (CI) calcd. for C18H24NO3Cl: 338 (M+H). Found: 338.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:19][C:18]=1[O:28][CH3:29]>O.CN(C)C=O.N1C=CC=CC=1>[CH3:29][O:28][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:17]=1[O:16][CH3:15])[CH:23]=[CH:24][C:25]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])=[O:26]
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
Into 15 ml of dimethylformamide were dissolved 1.51 g (0.011 mol) of anthranilic acid and 1.6 g of pyridine. To 10 ml of dimethylformamide were added in order 0.78 ml of thionyl chloride and 2.08 g (0.01 mol) of 3',4'-dimethoxycinnamic acid, during which the reaction system was stirred and cooled with ice and water. The resulting mixture was added dropwise to the above solution, during which the reaction system was stirred and cooled with ice and water. After the completion of the dropping, the reaction mixture was stirred for 30 minutes at the same temperature and then for 1 hour at room temperature. After the completion of the reaction, 80 ml of ice-water mixture was added thereto. The, air was introduced thereinto for 30 minutes, and crystals deposited were collected by filtration and recrystallized from chloroform to give 1.33 g (yield: 40.7%) of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid.