Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[S:11]([F:21])(=[O:20])([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)=[O:12]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([S:11]([F:21])(=[O:20])=[O:12])=[CH:14][CH:15]=2)[N:3]=1
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: N#Cc1cnc(Cl)nc1N
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(Nc2ccc(S(=O)(=O)F)cc2)nc1N
Yield: 35.7 %

Procedure:
A solution of 4-amino-2-chloro-5-cyanopyrimidine (8.0 g, 52 mmol) and sulphanilyl fluoride (9.07 g, 52 mmol) in NMP (155 ml) was heated at 120° C. for 24 hours. The mixture was allowed to cool and was diluted with water. The resulting precipitate was collected by filtration, washed with water and dried under vacuum at 60° C. for 2 hours. The crude product was recrystallized from ethyl acetate/hexane to give the title compound (5.45 g, 37%). NMR: 7.70 (s, 24H), 7.93 (d, 2H), 8.15 (d, 2H), 8.45 (s, 1H); m/z: 292 (MH)+.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6](=[O:13])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=2)[CH2:3][CH2:2]1.[ClH:14].Cl[O-].[Na+].S(=O)(O)[O-].[Na+]>O>[Cl:14][C:7]1[C:6](=[O:13])[NH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(=O)[nH]c(C2CC2)n1
Reactant: Cl
Agent: O=S([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Temperature: 9 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step A1 or A2) (184 g, 1.02 mol) in water (45 mL) and concentrated hydrochloric acid (292 g, 3 mol) at 8-12° C. was added dropwise aqueous sodium hypochlorite solution (8.4%, 1.02 kg, 1.15 mol) over 2 h so that with cooling the reaction mixture was maintained at 8-10° C. The mixture was then held at 10-12° C. for 1 h and the conversion was monitored by HPLC. When less than 5% of the starting material remained solid sodium bisulfite was added until a negative KI starch paper test was obtained. The mixture was cooled to 5° C., and the suspended product was isolated by filtration and washed with a minimum amount of cold water. The product was then dried to constant weight in vacuum-oven at 50° C. to afford the title compound (194 g); m.p. 189-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=2)[CH:7]=1.C1C(=O)N([Br:25])C(=O)C1>CN(C=O)C>[Br:25][C:10]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2cc3ccc(Cl)cn3n2)cc1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3cc(Cl)ccc3c2Br)cc1
Yield: 86.4 %

Procedure:
6-Chloro2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (2.48 g, 10.05 mmol) was dissolved in anhydrous DMF (160 ml) and treated with NBS (1.967 g) for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried and concentrated to give the title compound as a brown solid (2.827 g, 86%). (CDCl3) δ 7.19 (3H, t, J 9 Hz, H-3′+H-5); 7.48 (1H, d, J 9 Hz, H4); 8.05(2H, m, H-2′); 8.49 (1H, br s, H-7); Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.74 detection uv254.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][N:28]3[C:32](=[O:33])[CH2:31][CH2:30][C:29]3=[O:34])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:35]#[N:36])[CH:18]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:33]=[C:32]1[CH2:31][CH2:30][C:29](=[O:34])[N:28]1[CH2:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:18][C:19]([C:35]#[N:36])=[N:20]2)=[CH:25][CH:24]=1
Reactant: N#Cc1cc(Cl)c2ccc(CN3C(=O)CCC3=O)cc2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)cc2n1
Temperature: 100 °C

Procedure:
To a room temperature solution of 4-fluorophenylboronic acid (5.96 g, 42.6 mmol, 1.2 equiv.) in dioxane:water (10:1, 177 mL, 0.2 M) was added sodium bicarbonate (5.96 g, 71.0 mmol, 2.0 equiv.), 4-chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile (2-5, 10.6 g, 35.5 mmol), and Pd(PPh3)4 (4.1 g, 3.55 mmol, 0.1 equiv.). The resulting mixture was warmed to 100° C. for 4 hr. The reaction was then cooled to 0° C. and a precipitate formed. The solids were then collected by vacuum filtration and washed with water and cold acetonitrile to afford 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-6) which was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.115 (d, J=1.10 Hz, 1H); 7.897 (d, J=8.79 Hz, 1H); 7.655 (dd, J1=8.79 Hz, J2=1.83 Hz, 1H); 7.603 (s, 1H); 7.439-7.475 (m, 2H); 7.243-7.286 (m, 2H); 4.909 (s, 2H); 2.796 (s, 4H). LRMS m/z (M+H)+ 360.3 found, 360.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(=[O:36])C.C1C(=O)N(Br)C(=O)C1.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25][CH2:26][CH2:27][CH:28]4[CH2:29][O:36]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CCCCN(c1cc2nn(-c3ccc(Cl)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Reactant: CC(=O)O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCC3CO3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 118.7 %

Procedure:
To a solution of (i) (156 mg, 0.32 mmol) and acetic acid (37 μL, 0.64 mmol) in anhydrous 1,4-dioxane (15 mL) and water (20 mL) at 0° C. was added NBS (68 mg, 0.13 mmol) in a single portion. The reaction mixture was allowed to warm slowly to room temperature over 1 h 25 min whereupon aq. 1M NaOH solution (3 mL) was added and the reaction followed LCMS analysis. After 30 min, the reaction mixture was diluted with water (10 mL), extracted with EtOAc (3×10 mL) and the combined organics then dried (MgSO4) and concentrated in vacuo to obtain (ii) (191 mg, >100%). The crude product was used without further purification in the next step. ESI-MS m/z calculated for [M+H]+: 503.2. found: 503.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:12][CH:13]=O)=[CH:3]1.[Cl-].[C:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH+:24]=[C:23]([CH3:28])[C:22]2([CH3:30])[CH3:29])([OH:18])=[O:17].CCOCC>CN(C=O)C>[CH3:29][C:22]1([CH3:30])[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:16]([O-:18])=[O:17])[CH:20]=2)[N+:24]2[CH:23]=[CH:28][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[CH:12][C:13]1=2
Reactant: CC1=[NH+]c2ccc(C(=O)O)cc2C1(C)C
Reactant: Cn1cc(C=CC=O)c2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cn1cc(-c2cc[n+]3c(c2)C(C)(C)c2cc(C(=O)[O-])ccc2-3)c2ccccc21
Temperature: 120 °C
Yield: 17.6 %

Procedure:
A mixture of 3-(1-methyl-1H-indol-3-yl)prop-2-enal (2.37 g, 12.8 mmol) and 5-carboxy-2,3,3-trimethyl-3H-indolium chloride (3.06 g, 12.8 mmol) in 20 ml of DMF was heated at 120° C. for 17 h. After cooling, ether was added and the solids precipitated. The resulting solids was collected and further purified by silica gel chromatography (eluent: dichloromethane/methanol=10/1 to 2/1) to afford 0.83 g of a yellow powder.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([NH:19][C:20]([CH:22]3[CH2:25][CH2:24][N:23]3C(OC(C)(C)C)=O)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[N:4][NH:3]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([NH:19][C:20]([CH:22]3[CH2:25][CH2:24][NH:23]3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[N:4][NH:3]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC1C(=O)Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1)C1CCN1

Procedure:
A solution of EXAMPLE 112A (64 mg) in dichloromethane (4 mL) was treated with trifluoroacetic acid (2 mL) at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 339 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.64-1.73 (m, 4H), 2.36-2.44 (m, 2H), 2.46-2.53 (m, 2H), 2.57-2.69 (m, 1H), 2.81-2.93 (m, 1H), 3.94-4.04 (m, 1H), 3.98 (s, 2H), 4.08-4.20 (m, 1H), 5.07 (dd, J=9.49, 7.80 Hz, 1H), 7.03 (d, J=8.14 Hz, 1H), 7.30 (t, J=7.80 Hz, 1H), 7.41 (t, —1.70 Hz, 1H), 7.49 (dd, J=7.97, 1.53 Hz, 1H).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:4]1=2.[CH:19]([N:22]1[C:26]2[CH:27]=[CH:28][C:29](B(O)O)=[CH:30][C:25]=2[NH:24][C:23]1=[O:34])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:18][C:15]1[CH:16]=[CH:17][C:4]2[C:3](=[CH:2][C:29]3[CH:28]=[CH:27][C:26]4[N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:34])[NH:24][C:25]=4[CH:30]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:14]=1
Reactant: Fc1ccc2c(c1)OCc1ccccc1C2=CBr
Reactant: CC(C)n1c(=O)[nH]c2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)n1c(=O)[nH]c2cc(C=C3c4ccccc4COc4cc(F)ccc43)ccc21
Yield: 69.4 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3-fluoro-6,11-dihydro-dibenzo[b,e]oxepine (150 mg, 0.493 mmol), 1-isopropyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-boronic acid (103 mg, 0.468 mmol)(prepared according to Scheme IX by using isopropylamine in Step A), Na2CO3 (2M in water, 620 □L, 1.23 mmol), dioxane (4 mL), and Pd(PPh3)4 (29 mg, 0.025 mmol). Purify the crude product on silica gel (24 g), eluting with 25% to 50% THF/hexanes to afford 130 mg (69%) of the title compound as a yellow foam. HPLC (ISO80-10) t=3.86 min, 98%; MS [ES] 399 (M−H); 1H-NMR (CDCl3) δ 9.10 (s, 1H), 7.44 (m, 2H), 7.32 (t, 1H, J=7.5 Hz), 7.22 (t, 1H, J=7.5 Hz), 7.11 (d, 1H, J=7.5 Hz), 6.93 (d, 1H, J=8.4 Hz), 6.86 (s, 1H), 6.75 (d, 1H, J=8.4 Hz), 6.69 (s, 1H), 6.66 (td, 1H, J=11.7, 4.1 Hz), 6.52 (dd, 1H, J=10.3, 2.4 Hz), 5.92-4.73 (m, 2H), 4.66 (m, 1H), 1.51 (d, 6H, J=7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[N:30][N:31]([CH3:33])[N:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[N:30][N:31]([CH3:33])[N:32]=4)=[CH:24][CH:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnn(C)n2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnn(C)n4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (40% EtOAc/hexanes) gave the product as a pale yellow solid (0.106 g, 29% yield). MS: m/z 513.3 [M+H]+.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[NH:28][C:29]([NH2:31])=[NH:30]>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[NH:28][C:29]1[N:31]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:4]=[CH:3][N:30]=1
Reactant: CN(C)/C=C/C(=O)c1ccncc1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2ccncc2)n1

Procedure:
The title compound was prepared by condensation reaction between (2E)-3-(dimethylamino)-1-pyridin-4-ylprop-2-en-1-one and N-(2-methyl-5-nitrophenyl)guanidine nitrate, according to the procedure described in Step C of EXAMPLE 8. MS (M+1)=308.11.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20](Cl)=[O:21])[CH:18]=3)[NH:6][C:5]=2[C:4](=[O:23])[N:3]1[CH2:24][CH2:25][CH3:26].[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>C1COCC1>[O:21]=[C:20]([N:38]1[CH2:37][CH2:36][N:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:41])([F:42])[F:27])[CH:30]=2)[CH2:40][CH2:39]1)[CH2:19][N:17]1[CH:18]=[C:14]([C:7]2[NH:6][C:5]3[C:4](=[O:23])[N:3]([CH2:24][CH2:25][CH3:26])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=3[N:8]=2)[CH:15]=[N:16]1
Reactant: CCCn1c(=O)c2[nH]c(-c3cnn(CC(=O)Cl)c3)nc2n(CCC)c1=O
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC(=O)N4CCN(c5cccc(C(F)(F)F)c5)CC4)c3)nc2n(CCC)c1=O
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a solution of [4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyrazol-1-yl]-acetyl chloride (100 mg, 0.26 mmol) in THF (10 ml) was added TEA (53 mg, 0.53 mmol) and 1-(3-Trifluoromethyl-phenyl)-piperazine (66 mg, 0.29 mmol) at 0° C. and the mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC to obtain 8-(1-{2-Oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-1H-pyrazol-4-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (30 mg, 21%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][CH2:8][CH:9](O)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([CH:9]2[C:21]3[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:22]=3)[CH2:6][NH:7][CH2:8]2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(C(O)CNCc2ccc(C)cc2)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCc3ccc(C)cc32)cc1OC
Yield: 98.3 %

Procedure:
530 mg of α-[[(4-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 4 ml of trifluoroacetic acid, and after adding thereto 0.12 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 30 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. After adding chloroform, the mixture was basified by addition of 28% aqueous ammonia, by a separating procedure, the chloroform layer was collected, was washed with water once, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 490 mg of 4-(3,4-dimethoxyphenyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline (melting point: 94°-96° C.).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[NH2:16][CH2:17][CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]3[CH2:29][CH2:30][C:31](=[O:34])[NH:32][N:33]=3)[CH:25]=[CH:24][C:22]=2[N:23]=1>>[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][NH:16][CH2:17][CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]3[CH2:29][CH2:30][C:31](=[O:34])[NH:32][N:33]=3)[CH:25]=[CH:24][C:22]=2[N:23]=1)[CH:2]=[CH2:3]
Reactant: NCCc1nc2ccc(C3=NNC(=O)CC3)cc2[nH]1
Reactant: C=CCOc1ccccc1OCC1CO1
Product: C=CCOc1ccccc1OCC(O)CNCCc1nc2ccc(C3=NNC(=O)CC3)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 1-(2-allyloxy-phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [N:1]1([C:6]2([C:10]([O:12]CC)=[O:11])[CH2:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1.O1CCCC1.[OH-].[Na+]>O>[N:1]1([C:6]2([C:10]([OH:12])=[O:11])[CH2:7][CH2:8][CH2:9]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)C1(n2cccn2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(n2cccn2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
To ethyl 1-(1H-pyrazol-1-yl)cyclobutanecarboxylate (688 mg, 3.54 mmol) were added tetrahydrofuran (8 mL) and water (0.9 mL). Aqueous sodium hydroxide (1N, 4 mL, 4 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and to the residue was added aqueous hydrochloric acid (1N, 1 mL). The mixture was extracted with dichloromethane (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (108.9 mg). The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12][C:13]#[N:14])[CH:3]=1.[H-].[Na+].[C:17](OCC)(=[O:19])[CH3:18].O>C1COCC1>[F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]([C:17](=[O:19])[CH3:18])[C:13]#[N:14])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#CCc1cc(F)c2c(c1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(C#N)c1cc(F)c2c(c1)OCCO2
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)acetonitrile (0.40 g, 2.10 mmol) in THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) and ethyl acetate (2.05 ml, 21.0 mmol) and the mixture was stirred at 60° C. for 2 h. After cooling to 0° C., water was added (25 mL) and the aqueous layer was washed with dichloromethane (3×15 mL), acidified with 1N HCl to pH 3 and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (30 mL) then dried with sodium sulfate, filtered and concentrated to give 2-(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-oxobutanenitrile as an orange solid (0.37 g; 75% yield). 1H NMR (400 MHz, d6-DMSO) δ 7.05 (dd, 1H), 6.93 (br. s, 1H), 4.30 (m, 5H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][CH:7]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[C:8]([NH:10][C:11]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:9].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:6][CH:7]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:36])([F:35])[F:37])[CH:25]=1)[C:8]([NH:10][C:11]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][CH2:13][C:14](=[CH2:1])[CH2:15][CH2:16]1)=[O:9]
Reactant: CC(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(NC(=O)C(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
n-Butyllithium (1.6 Mol solution in hexanes, 10.3 mL) was added slowly to a stirred, cooled (0° C.) suspension of methyl triphenylphosphonium bromide (5.86 g, 16.4 mmol) in tetrahydrofuran (60 mL) and the mixture was stirred at room temperature for 3 hours. The mixture was cooled to 0° C. and (RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide (Example 3, 3.0 g, 6.56 mmol) in tetrahydrofuran (20 mL) was added. The mixture was stirred at room temperature for 1 hour, then under reflux for 3 hours. The mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a short column of silica gel, eluting with dichloromethane, to give the title compound as a colorless solid (2.27 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.75 (2H, s), 7.26–7.20 (5H, m), 5.59 (1H, s), 4.68 (2H, m), 3.70 (1H, d, J 7.1 Hz), 2.53–2.45 (1H, m), 2.38–2.31 (1H, m), 2.29–2.04 (4H, m), 2.00–1.85 (2H, m), and 1.52 (3H, d, J, 7.1 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Cl)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[CH:11][CH:10]=1
Reactant: O=C1CNCCN1
Reactant: ClCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CN(CCc2ccc(Cl)cc2)CCN1
Temperature: 85 °C
Yield: 60.8 %

Procedure:
Piperazinone (1.04 g, 10.4 mmol), 1-chloro-4-(2-chloroethyl)benzene (2.28 g, 10.4 mmol) and K2CO3 (1.72 g, 12.4 mmol) were combined in DMSO (12 mL) and heated to 85° C. for 2 h. The mixture was partitioned between H2O (20 mL) and CH2Cl2 (20 mL), and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organics were concentrated, and the residue was dissolved in 2 N HCl (50 mL). This acidic mixture was washed with CH2Cl2 (3×20 mL) and then made basic with 6 N NaOH. The basic mixture was extracted with CH2Cl2 (3×20 mL), and the extracts were combined, dried and concentrated to provide the title compound (1.51 g, 60%) as an orange solid: 1H NMR (500 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 3.14-3.10 (m, 2H), 2.96 (s, 2H), 2.74 (t, J=6.6 Hz, 2H), 2.62-2.53 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21][CH3:22])[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[OH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.[O-]CC.[Na+]>>[OH:5][C:4]([C:7]([F:8])([F:9])[F:10])([CH2:3][C:2]([CH3:11])([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21][CH3:22])[CH:13]=1)[CH3:1])[CH2:6][N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24](=[O:23])[CH:25]=[CH:26]1
Reactant: CSc1cc2c(c(C(C)(C)CC3(C(F)(F)F)CO3)c1)OCC2
Reactant: Oc1ccnc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Product: CSc1cc2c(c(C(C)(C)CC(O)(Cn3ccc(=O)c4ccccc43)C(F)(F)F)c1)OCC2

Procedure:
7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methylsulfanyl-2,3-dihydrobenzofuran was reacted with 4-hydroxyquinoline and sodium ethoxide according to Example 35 to give 1-[2-hydroxy-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-trifluoromethylpentyl]-1H-quinolin-4-one.