Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/O)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60][C:61]3[N:62]=[C:5]([C:2]4([CH3:1])[CH2:4][CH2:3]4)[O:7][N:64]=3)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4(C)CC4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-methylcyclopropanecarboxylic acid (6 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (31 μL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min, 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A34) as an off white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.87 (s, 1H), 9.13 (s, 1H), 8.05 (s, 1H), 7.87 (s, 1H), 7.37 (dd, J=8, 2 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.22 (d, J=8 Hz, 2H), 3.70 (s, 3H), 2.75 (s, 3H), 2.07 (s, 3H), 1.47 (s, 3H), 1.27 (m, 2H), 1.08 (m, 2H). MS m/z 402.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16]C)=[O:15])=[CH:7][C:6]=2[CH:18]=1>COCCOC.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([OH:16])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: O=C(O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (700 mg) in 1,2-dimethoxyethane (15 ml) and 6N hydrochloric acid was refluxed for 18 hours and cooled to room temperature. The solvent was evaporated under reduced pressure to give colorless crystals, which were collected by filtration. The crystals were washed with water, 2-propanol and diisopropylether to give colorless crystals of 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (634 mg).
Reaction SMILES: [Mg].[CH2:2](Cl)[C:3](=[CH2:5])[CH3:4].[C:7]([CH:10]1[C:15]([CH3:17])([CH3:16])[CH:14]2[CH2:18][CH:11]1[CH:12]=[CH:13]2)(=[O:9])[CH3:8].[Cl-].[NH4+]>C(OCC)C>[CH2:2]([C:7]([CH3:8])([CH:10]1[C:15]([CH3:16])([CH3:17])[CH:14]2[CH2:18][CH:11]1[CH:12]=[CH:13]2)[OH:9])[C:3](=[CH2:5])[CH3:4]
Reactant: CC(=O)C1C2C=CC(C2)C1(C)C
Reactant: C=C(C)CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C(C)CC(C)(O)C1C2C=CC(C2)C1(C)C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
Into a 1 liter reaction flask equipped with a reflux condenser, thermometer, stirrer, dropping funnel and nitrogen inlet tube are placed 12 g (0.5 moles) of magnesium turnings and 250 cc anhydrous diethyl ether. Over a 2 hour period, 45.3 g (0.5 moles) of methallyl chloride is added. The Grignard solution is stirred for 1/2 hour and 28 g of 2-acetyl-3,3-dimethyl-5-norbornene is added over a 20 minute period. The mixture is stirred at reflux for 1/2 hour and then is hydrolyzed by the addition of saturated ammonium chloride solution. The organic layer is washed with water and dried over magnesium sulfate. The mixture is then filtered and the solvent evaporated to yield 40 g of an oil, which is then fractionated on a micro Vigreux column after adding thereto 5 g Primol® and a trace quantity of Ionox®.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([F:28])[CH:34]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(-c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VI as described above, the arylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3-fluorophenylboronic acid gave the title compound. ES-MS m/e (%): 475.0 (M+H+).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:10]([C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([CH2:24][CH2:25][CH3:26])[C:22]=1[OH:23])[N:19]=[C:18]([C:27]([O:29][CH3:30])=[O:28])[CH:17]=[C:16]2Cl)(=[O:12])[CH3:11]>>[C:10]([C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([CH2:24][CH2:25][CH3:26])[C:22]=1[OH:23])[N:19]=[C:18]([C:27]([O:29][CH3:30])=[O:28])[CH:17]=[C:16]2[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: Oc1ccccc1
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Agent: [K+]
Agent: [OH-]
Product: CCCc1c(O)c(C(C)=O)cc2c(Oc3ccccc3)cc(C(=O)OC)nc12
Reaction time: 1.5 h

Procedure:
Phenol (10.0 g) which had been crushed in a mortar and pestle, was added to crushed potassium hydroxide (0.36 g) in a flask which was immersed in an oil bath. This was stirred at 60°-65° C. for 5 minutes before methyl 6-acetyl-4-chloro-7-hydroxy-8-propyl-quinoline-2-carboxylate (1.0 g) was added. The whole was stirred at 60°-65° C. for 1.5 hours and the phenol was then removed by steam distillation.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:41]([C:43]1[C:48]([CH3:49])=[CH:47][C:46](/[CH:50]=[CH:51]/[C:52]([O:54][CH3:55])=[O:53])=[CH:45][C:44]=1[CH3:56])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:55][O:54][C:52](/[CH:51]=[CH:50]/[C:46]1[CH:45]=[C:44]([CH3:56])[C:43](/[CH:41]=[CH:2]/[C:3]2[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:5][C:4]=2[N+:19]([O-:21])=[O:20])=[C:48]([CH3:49])[CH:47]=1)=[O:53]
Reactant: O=C(OCc1ccccc1)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: COC(=O)/C=C/c1cc(C)c(C=O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1cc(C)c(/C=C/c2ccc(C(=O)OCc3ccccc3)cc2[N+](=O)[O-])c(C)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of benzyl 4-bromomethyl-3-nitrobenzoate (2.06 g, 5.88 mmol) and triphenylphosphine (1.54 g, 5.87 mmol) in DMF (10 mL) was heated at 100° C. for 1 h. To this solution was added methyl (E)-3-(4-formyl-3,5-dimethylphenyl)-acrylate (1.28 g., 5.86 mmol) and potassium carbonate (1.63 g, 11.8 mmol) and the mixture was heated and stirred at 100° C. for 18 h. The reaction was poured into ethyl acetate and extracted with water once and brine.five times. The organic layer was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography using a 0-40% gradient of heptane/ethyl acetate to give benzyl 4-{(E)-2-[4-((E)-2-methoxycarbonylvinyl)-2,6-dimethylphenyl]-vinyl}-3-nitrobenzoate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([CH3:32])=[C:16]([Cl:33])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.Cl.O=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1.C([BH3-])#N.[Na+]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH2:22][CH2:21][N:20]([CH:36]5[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]5)[CH2:19][C:18]=4[C:17]([CH3:32])=[C:16]([Cl:33])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: Cc1c(Cl)cc(C(C)n2nc(C)c3c(N)ncnc32)c2c1CN(C(=O)OC(C)(C)C)CCO2
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(Cl)cc(C(C)n2nc(C)c3c(N)ncnc32)c2c1CN(C1CN(C(=O)OC(C)(C)C)C1)CCO2
Temperature: 60 °C
Yield: 3.1 %

Procedure:
tert-Butyl 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (100 mg, 0.2 mmol) was treated with 4 N HCl in dioxane (1 mL), and then the solvent was evaporated. The residue was stirred in methanol (5 mL) and tert-butyl 3-oxoazetidine-1-carboxylate (140 mg, 0.84 mmol) was added. Sodium cyanoborohydride (120 mg, 1.9 mmol) was added and the mixture was warmed to 60° C. for 1.5 hours. Purification by preparative LCMS (pH 10) gave the desired compound (3.3 mg, 10%). LCMS calculated for C26H35ClN7O3 (M+H)+: m/z=528.2; found: 528.3. 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.33 (s, 1 H), 6.33 (m, 1 H), 4.00 (m, 2 H), 3.82 (m, 1 H), 3.74 (m, 2 H), 3.63 (m, 3 H), 3.41 (m, 1 H), 2.76 (m, 2 H), 2.58 (s, 3 H), 2.37 (s, 3 H), 1.79 (m, 3 H), 1.42 (s, 9H).
Reaction SMILES: Cl.CN.CS([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH:11]=[CH:10][N:9]=1)(=O)=O.C[CH2:31][N:32](C(C)C)C(C)C>CC(O)C>[CH3:31][NH:32][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CS(=O)(=O)c1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CC(C)O
Product: CNc1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of methylamine hydrochloride (0.863 g, 12.8 mmol), 2-(methylsulfonyl)-4-(2-(4-nitrophenoxy)phenyl)pyrimidine (0.791 g, 2.13 mmol) in iPrOH was added n,n-diisopropylethylamine (2.60 ml, 14.9 mmol). The reaction was sealed and heated to 70 deg. C. overnight. The resulting clear yellow solution was judged complete by LCMS in the morning. The reaction was cooled to ambient temperature, resulting in the formation of whit crystals. Filter, rinsing with isopropanol. Concentrate filtrate, partition between EtOAc and 1N NaOH. Dry over anhyd. Na2SO4, filter, concentrate to give N-methyl-4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine as a light yellow solid. MS m/z=323 [M+1]+. Calc'd for C17H14N4O3: 322.32.
Reaction SMILES: C([C:4]1[C:9]2[CH:10]=[CH:11][N:12]([C:13]([C:15]3[C:23]([Cl:24])=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=3[Cl:25])=[O:14])[C:8]=2[CH:7]=[CH:6][N:5]=1)(=O)C.[N:26]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[C:13]([NH:12][C:4]1[C:9]2[CH:10]=[CH:11][N:12]([C:13]([C:15]3[C:16]([Cl:25])=[CH:17][C:18]([C:19]([NH:35][CH2:34][CH2:33][CH2:32][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:21])=[CH:22][C:23]=3[Cl:24])=[O:14])[C:8]=2[CH:7]=[CH:6][N:5]=1)(=[O:14])[CH3:15]
Reactant: NCCCN1CCOCC1
Reactant: CC(=O)c1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Product: CC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)NCCCN2CCOCC2)cc1Cl

Procedure:
This was prepared analogously from 4-[(4-acetyl-1H-pyrrolo[3,2-c]pyridin-1-yl)carbonyl]-3,5-dichlorobenzoic acid and 3-(morpholin-4-yl)propylamine.
Reaction SMILES: CI.[F:3][C:4]([F:18])([CH2:14][CH2:15][CH2:16][OH:17])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:19]C(C)([O-])C.[K+]>O1CCCC1>[F:3][C:4]([F:18])([CH2:14][CH2:15][CH2:16][O:17][CH3:19])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: OCCCC(F)(F)COCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COCCCC(F)(F)COCc1ccccc1
Reaction time: 8 h

Procedure:
Excess methyl iodide (17 g, 120 mmoles) is added to the alcoholate previously prepared from 2,2-difluoro-1-benzyloxy-5-hydroxypentane (9.8 g, 42.6 mmoles) and potassium t-butoxide (5.6 g, 50 mmoles) in dry tetrahydrofuran (50 ml). The reaction mixture is kept at room temperature overnight, concentrated under vacuum, and the residue is deluted with water and ether. Usual extraction gives the title compound which is purified by chromatography on silica (ethyl acetate/petroleum ether: 20/80, RF: 0.9; 7.4 g, 71%).
Reaction SMILES: [N:1]1([CH2:10][C@@H:11]([CH3:36])[O:12][C:13]2[CH:14]=[C:15]([NH:32][C:33](=[O:35])[CH3:34])[CH:16]=[CH:17][C:18]=2[S:19](=[O:31])(=[O:30])[NH:20][CH:21]2[CH2:25][C:24](=[O:26])[O:23][CH:22]2[O:27]CC)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[ClH:37]>C(#N)C>[ClH:37].[C:33]([NH:32][C:15]1[CH:16]=[CH:17][C:18]([S:19]([NH:20][CH:21]([CH:22]=[O:27])[CH2:25][C:24]([OH:26])=[O:23])(=[O:31])=[O:30])=[C:13]([O:12][C@H:11]([CH3:36])[CH2:10][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[N:2]2)[CH:14]=1)(=[O:35])[CH3:34]
Reactant: CCOC1OC(=O)CC1NS(=O)(=O)c1ccc(NC(C)=O)cc1O[C@H](C)Cn1ncc2ccccc21
Agent: Cl
Solvent: CC#N
Product: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(O[C@H](C)Cn2ncc3ccccc32)c1
Yield: 65.5 %

Procedure:
0.103 g (0.199 mmol) N-[3-((R)-2-Indazol-1-yl-1-methyl-ethoxy)-4-(2-ethoxy-5-oxo-tetrahydro-furan-3-ylsulfamoyl)-phenyl]-acetamide was stirred in 10 mL of a mixture of 1:1 5% HCl (aq):acetonitrile at room temperature 18 hr. TLC analysis indicated complete reaction. The solvent was removed under a nitrogen flow for 5 hr. The yellow residue was triturated with a 2:1 mixture of acetone:ether. The precipitate was filtered and dried at 35° C. 18 hr to yield 0.059 g (0.113 mmol, 65.5%) of 3-[4-acetylamino-2-((R)-2-indazol-1-yl-1-methyl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid hydrochloric acid salt. Analysis calculated for C22H24N4O7S.0.91 HCl (521.70): C, 50.33; H, 4.80; N, 10.67. Found: C, 50.27; H, 5.01; N, 10.40.
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH2:8]O)[CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:14]>C(Cl)Cl>[CH:1]1([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH2:8][Br:14])[CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cccc(C2CCC2)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1cccc(C2CCC2)c1
Yield: 89 %

Procedure:
According to example 17, 1.29 g of 3-cyclobutylbenzyl alcohol was treated with 0.26 mL of PBr3 in 15 mL of anhydrous CH2Cl2 to afford 1.69 g of crude product (92% pure by 1H-NMR). This material was purified by flash chromatography on 65 g of silica gel (hexane) to afford 1.59 g (89%) of 3-cyclobutyl benzyl bromide as a clear liquid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]1.Br.[IH:23]>>[IH:23].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: Br
Agent: I
Product: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (4.63 g, 16 mmol) and 48% hydrobromic acid (75 mL). Heat to reflux. After 1.5 hours, cool and evaporate in vacuo to give a solid. Add 47% hydriodic acid (30 mL) and heat at about 90° C. After 30 minutes cool to obtain a solid. Collect the solid by filtration, rinse with ethanol and diethyl ether, and dry to give the title compound: mp; >290° C.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:28])[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:19][C:18]=1[C:29]([F:32])([F:31])[F:30]>>[CH3:26][N:25]([CH3:27])[CH2:24][C@@H:23]([NH:28][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:20]1[CH:21]=[CH:22][C:17]([F:16])=[C:18]([C:29]([F:30])([F:31])[F:32])[CH:19]=1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C)C[C@@H](N)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Product: CN(C)C[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C(F)(F)F)c1

Procedure:
Compound 50 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-1-(4-Fluoro-3-trifluoromethyl-phenyl)-N2,N2-dimethyl-ethane-1,2-diamine hydrochloride to give the title compound as a white solid. LC/MS [423 (M+H)]; 1H NMR (400 MHz, Acetonitrile-d3) δ 10.31 (s, 1H), 8.96 (d, 1H), 8.55-8.42 (m, 3H), 7.90-7.73 (m, 2H), 7.33 (t, 1H), 6.63 (s, 1H), 5.55 (s, 1H), 3.20 (s, 1H), 2.81 (s, 1H), 2.17 (s, 6H).
Reaction SMILES: [C:1]1([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[C:9]([NH2:23])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.O1C=CC[CH2:27]1.O>CO>[C:1]1([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[C:9]([NH:23][CH3:27])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Reactant: C1=COCC1
Agent: CN
Solvent: O
Solvent: CO
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1

Procedure:
In this example, a mixture containing 0.5 g of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran ("dihydrofuran starting material") and 25 ml of aqueous 40 wt. % methylamine in 10 ml of methanol was refluxed for 18 hours. The mixture was analyzed by thin-layer chromatography for the dihydrofuran starting material. Another 10 ml of aqueous 40 wt. % methylamine was added and the mixture refluxed for about four hours. The mixture was cooled, poured into 100 ml of water and extracted several times with ethyl ether. The organic extracts were dried over magnesium sulfate, concentrated in vacuo and chromatographed using 3% tetrahydrofuran/chloroform as eluent to yield 0.36 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([C:22]([NH2:24])=[O:23])=[C:15]2Cl.C(O)(=O)C.C(O)C>C(O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH3:10])[CH:13]=3)[N:18]=[CH:17][C:16]=2[C:22]([NH2:24])=[O:23])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1ccc2ncc(C(N)=O)c(Cl)c2c1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2ncc(C(N)=O)c(Nc3ccc(F)cc3C)c2c1
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-2-methylaniline (0.025 mmol), 6-methoxy-4-chloro-3-quinolinecarboxamide (0.025 mmol), 50 μl 20% Acetic acid/Ethanol and 250 μl ethanol was refluxed for four hours. After cooling to room temperature the solvent was removed in vacuu.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])/[C:3](/[CH3:15])=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]([F:16])([F:17])/[C:3](/[CH3:15])=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(/C=C(\C)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(C(=O)O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred mixture of methyl (E)-4-(3,3,3-trifluoro-2-methylprop-1-enyl)benzoate (60 mg, 0.25 mmol) in THF (5 mL) and MeOH (5 mL) was added a 2N NaOH solution (1 mL). The mixture was stirred at room temperature for 10 h. After removal of the organic solvent in vacuo, the mixture was treated with water and acidified with 1N HCl to pH 2-3. The mixture was extracted with EtOAc (20 mL×3). The combined extracts were washed with brine, dried (Na2SO4), and evaporated. The residue was purified with column to give (E)-4-(3,3,3-trifluoro-2-methylprop-1-enyl)benzoic acid as a white solid. LC-MS: tR=3.04 min, m/z=229 (M−1).
Reaction SMILES: [CH:1]1(/[C:4](/[CH:11]=[CH:12]/[C:13]2([OH:31])[C:24]([CH3:29])([C:25]([F:28])([F:27])[F:26])[CH2:23][C:16]3(OC(C)C(C)[O:17]3)[CH:15]=[C:14]2[CH3:30])=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.O>CC(C)=O.Cl>[CH:1]1(/[C:4](/[CH:11]=[CH:12]/[C:13]2([OH:31])[C:24]([CH3:29])([C:25]([F:28])([F:27])[F:26])[CH2:23][C:16](=[O:17])[CH:15]=[C:14]2[CH3:30])=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)C1CC1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC(=O)CC1(C)C(F)(F)F)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
Ethyl (2Z,4E)-3-cyclopropyl-5-[8-hydroxy-2,3,7,9-tetramethyl-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-yl]penta-2,4-dienoate (40 mg, 0.09 mmol) was dissolved in acetone (4 ml) under argon in a round-bottom flask, and a few drops of conc. hydrochloric acid were added. The resulting reaction solution was stirred at room temperature for 4 h and then water was added. After removing acetone under reduced pressure, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2Z,4E)-3-cyclopropyl-5-[1-hydroxy-2,6-dimethyl-4-oxo-6-(trifluoromethyl)cyclohex-2-en-1-yl]penta-2,4-dienoate (15 mg, 45% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.88 (d, 1H), 6.37 (d, 1H), 6.01 (s, 1H), 5.64 (s, 1H), 4.17 (q, 2H), 2.92 (d, 1H), 2.52 (d, 1H), 2.39 (br. s, 1H, OH), 1.98 (s, 3H), 1.59 (m, 1H), 1.30 (t, 3H), 1.28 (s, 3H), 0.88 (m, 2H), 0.59 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21].C([BH3-])#N.[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:22][CH2:19][CH2:20][CH3:21])[CH:12]=2)[CH:3]=1
Reactant: CCCN
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 76.9 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), n-propylamine (140 μL, 101 mg, 1.7 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[3-(propylaminomethyl)phenoxy]benzonitrile fumarate (250 mg, 78%) as a white solid.