Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:34])[NH:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(F)c1OC

Procedure:
In the same way as in Example 29, 210 mg (0.64 mmol) of (2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 132 mg (0.97 mmol) of 5-aminoquinolin-2(1H)-one and 0.27 ml of titanium tetraethoxide are reacted to give 5-{[(2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one. 234 mg of crude imine are cyclized in the same way as in Example 29 at −40° C. with 5 ml (5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 33-100%) yields 25 mg of the desired product.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][CH2:8][O:9][C:10]([N:12]1[N:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:23][CH2:22][CH2:21]3)[CH:15]([CH3:40])[S:14][C:13]1=[O:41])=[O:11].N1C=CC=CC=1>ClCCl>[CH2:1]([N:3]([CH2:7][CH2:8][O:9][C:10]([N:12]1[N:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:23][CH2:22][CH2:21]3)[CH:15]([CH3:40])[S:14][C:13]1=[O:41])=[O:11])[CH2:4][CH3:5])[CH3:2]
Reactant: COc1ccc(C(=O)N2CCCc3cc(C4=NN(C(=O)OCCCl)C(=O)SC4C)ccc32)cc1OC
Reactant: CCNCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)CCCN3C(=O)c2ccc(OC)c(OC)c2)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2.5 g of diethylamine dissolved in 30 ml of dichloromethane are added dropwise with stirring to a solution of 10 g of 3-[2-chloroethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 9 ml of pyridine in 100 ml of dichloromethane and the mixture is subsequently stirred at 20° C. for one hour. The solvent is removed and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Cl:7].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:44][C@@H:45]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]([F:68])([F:67])[F:66])[CH2:46][N:47]1[C:55](=[O:56])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]1=[O:57]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:44][C@@H:45]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:66])[F:67])[CH2:46][N:47]2[C:55](=[O:56])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]2=[O:57])=[O:10])[S:5][C:6]=1[Cl:7]
Reactant: O=C(O)c1cc(Br)c(Cl)s1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1cc(Br)c(Cl)s1
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-5-chloro-2-thiophenecarboxylic acid (1.3 g, 5.42 mmol), PyBrOP (3 g, 6.5 mmol) and diisopropylethyl amine (4.7 mL, 27.1 mmol) in DCM (54 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (2.0 g, 5.42 mmol) [prepared in Preparation 6]. After 1 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and used directly: LCMS (ES) m/z=572 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[B:16]([O:25]C(C)C)([O:21]C(C)C)[O:17]C(C)C.[ClH:29]>C1COCC1>[ClH:29].[CH3:9][N:8]([CH3:10])[C:5]1[N:4]=[CH:3][C:2]([O:17][B:16]([OH:25])[OH:21])=[CH:7][N:6]=1
Reactant: CN(C)c1ncc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)c1ncc(OB(O)O)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-bromo-2-dimethylaminopyrimidine (2.0 g, 9.9 mmol: Bull. Chem. Soc. Jpn., 72, 2523 (1999)) dissolved in THF (25 ml) was added 1.56 M of n-butyl lithium (hexane solution, 7.0 ml, 10.9 mmol) under cooling with a dry ice-acetone bath. After stirring the mixture for 40 minutes, a solution of triisopropyl borate (3.5 ml, 0.15 ml) dissolved in THF (6 ml) was added to the reaction mixture. The temperature of the mixture was raised to room temperature, hydrochloric acid was added to the mixture, and then the solvent was removed. The residue was triturated by methanol-diethyl ether to give 2-dimethylamino-5-pyrimidinylboric acid hydrochloride (2.26 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]#[C:12]Cl)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].C(O)(=O)C>O1CCCC1.[Cu]>[CH3:1][O:2][C:3]([C:5]1([C:11]#[CH:12])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(C#CCl)CCOCC1
Agent: [Cu]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#CC1(C(=O)OC)CCOCC1
Temperature: 60 °C

Procedure:
4-Chloroethynyl-tetrahydro-pyran-4-carboxylic acid methyl ester (1.01 g, 5 mmol) and copper powder (1.6 g, 25 mmol) were suspended in tetrahydrofuran (100 mL). Acetic acid (15 mL) was added and the reaction mixture was heated to 60° C. for 3 hours. After this time, the reaction mixture was poured onto water (copper powder was filtered off with the use of the filtration paper) and extracted with diethyl ether (3×50 mL). The combined organic extracts were washed with saturated solution of ammonium chloride (3×50 mL), with saturated solution of sodium bicarbonate (2×50 mL) and with water (50 mL). This water phase was extracted with diethyl ether (50 mL). Combined organic extracts were washed with brine (50 mL) and dried over magnesium sulfate, filtered through a 2 cm layer of silica gel (silica gel layer was washed with 50 mL of ethyl acetate), and concentrated under reduced pressure. After drying under high vacuum for one day, the title compound was isolated (0.84 g, quantitative yield) as a colorless oil. Rf=0.37, 30% ethyl acetate in iso-hexanes, phosphomolybdic acid in ethanol. LCMS (m/z) 169.0 [M+H]′ Tr=2.43 min (Gemini 5u C18 110 Å, 50×4.60 mm 5 micron column, 3.5 min, 2 ml/min, 5-100% acetonitrile/water, 0.1% acetic acid modifier gradient). 1H NMR (400 MHz, CDCl3): δ 3.80-3.67 (m, 4H), 3.73 (s, 3H), 2.34 (s, 1H), 1.98 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=O)(=[O:3])[CH3:2].Cl>CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:6]=1[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCc1ccc(F)cc1NC(C)=O
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1cc(F)cc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in (4) above (42 gm) was dissolved into 100 ml of methanol. After the addition of 200 ml of 1N hydrochloric acid, the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated to 200 ml and, after acidifying with the addition of concentrated hydrochloric acid, extracted three times with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated, and to the residue were added 100 ml of dichloromethane, then 17 gm of sodium carbonate and 12 ml of thionyl chloride. The mixture was heated under reflux for 2 hours, and then cooled to room temperature to remove insoluble substances by filtration. The filtrate was concentrated and 200 ml of 1,2-dichloromethane and 40 gm of aluminum chloride were added to the residue. The mixture was stirred for 3 hours at 70° C., then for 1 hour at 90° C. The reaction product was poured into ice-cold water and extracted with chloroform. The extract was washed with water, saturated sodium bicarbonate, and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using chloroform-ethyl acetate (7:3) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to obtain 17 gm of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](Br)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>COCCOC.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>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34](=[O:36])(=[O:35])[NH2:37])[CH:29]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)c2scc(-c3ccc(F)c(Cl)c3)c12
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
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: CN(C)C=O
Solvent: COCCOC
Product: Nc1ncc(-c2cccc(S(N)(=O)=O)c2)c2scc(-c3ccc(F)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 14 h
Yield: 20.2 %

Procedure:
The mixture of 4-amino-7-bromo-3-(3-chloro-4-fluoro-phenyl)thieno[3,2-c]pyridine (40 mg, 0.112 mmol), Pd(PPh3)4 (19 mg, 10 mol %), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (36.8 mg, 0.224 mmol) and 2M Na2CO3 aqueous solution (0.28 ml, 0.56 mmol) in 2 ml of DME was stirred for 14 hours at 80° C. As starting material remained, same amount of reagents described above and DMF (2 ml) were added and stirred for 5 hours at 100° C. The resultant mixture was directly applied to SCX (Varian, 5 g) and eluted with 1N NH3 in CHCl3 and MeOH was collected, and the eluant was concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford the titled compound (9.8 mg) 1H NMR (400 MHz, DMSO-d6) ppm 8.12 (dd, J=1.8 Hz, 1H), 8.0 s, 1H), 7.91 (ddd, J=1.5, 1.5, 7.6 Hz, 1H), 7.85 (ddd, J=1.4, 1.4, 7.1 Hz, 1H), 7.75 (dd, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.57 (dd, J=9.0 Hz, 1H), 7.51 (ddd, J=2.2, 4.9, 8.5 Hz, 1H), 7.45 (s, 2H), 5.66 (s, 2H). MS: m/z 434 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:11][O:10][C:9](=[O:12])[C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[CH3:31][NH2:32]>CO>[OH:10][CH2:11]/[C:7](/[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[C:8](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH:15][CH:14]=1)\[C:9]([NH:32][CH3:31])=[O:12]
Reactant: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CN
Solvent: CO
Product: CNC(=O)/C(=C(\CO)c1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 86 %

Procedure:
A solution of 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (1.0 g, 0.002 mol) and MeNH2 in MeOH (25 mL) was refluxed for 1 h. The reaction mixture was concentrated in vacuo to afford (Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)but-2-enamide (920 mg, 86%) as a solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[CH:19]1([NH:25][C:26](=[O:29])[CH2:27]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:11]([CH2:10][CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:27][C:26]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:29])[CH2:3][CH2:4]1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: O=C(CCl)NC1CCCCC1
Product: O=C(CNC1CCN(CCCC(=O)c2ccccc2)CC1)NC1CCCCC1

Procedure:
Using a procedure analogous to Example 1 4-amino-1-(4-phenyl-4-oxobutyl) piperidine may be reacted with N-cyclohexylchloracetamide to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:14][C:11]1([F:13])[CH2:12][NH:8][CH:9]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH2:10]1
Reactant: COC(=O)c1ccc(OCC2CC(F)(F)CN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CC(F)(F)CN2)cc1
Reaction time: 3 h
Yield: 90.9 %

Procedure:
A mixture of methyl 4-[1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethoxy]benzoate (830 mg, 2.23 mmol) and TFA (5 ml) in CH2Cl2 (5 ml) was stirred for 3 h and concntrated in vacuo. The residue was made basic with sat. NaHCO3 and extracted with CHCl3 (2×200 ml). The combined extracts were dried over K2CO3 and concntrated in vacuo to give methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)benzoate (550 mg, 91%) as a pale yellow solid. 1H-NMR (CDCl3) δ2.19 (m, 1 H), 2.43 (m, 1 H), 3.19-3.41 (m, 2 H), 3.77 (m, 1 H), 3.89 (s, 3 H), 4.00-4.09 (m, 2 H), 6.92 (d, J=9.0 Hz, 2 H), 7.99 (d, J=9.0 Hz, 2 H); MS (FAB) m/z 272 (M++1); Anal. Calcd. for C13H15F2NO3: C, 57.56; H, 5.57; N, 5.16. Found: C, 57.65; H, 5.67; N, 5.16.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:21]([NH:37][CH2:38][CH2:39][C:40](Cl)=[O:41])([C:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:29]([N:30]([CH3:32])[CH3:31])[C:28]=2[CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22]>CN(C)C=O>[S:21]([NH:37][CH2:38][CH2:39][C:40]([C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[S:8]([N:11]=[N+:12]=[N-:13])(=[O:10])=[O:9])=[O:41])([C:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:29]([N:30]([CH3:32])[CH3:31])[C:28]=2[CH:27]=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(N)cc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCCC(=O)Cl)cccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1cccc2c(S(=O)(=O)NCCC(=O)c3ccccc3S(=O)(=O)N=[N+]=[N-])cccc12
Reaction time: 24 h

Procedure:
To 152 mg (0.8 mmol) of para-amino-benzenesulfonyl azide dissolved in 5 mL dimethylformamide was added 0.11 mL (6 mmol) triethylamine, then 0.5 mmol N-Dansyl 3 aminopropanoyl chloride dissolved in 10 mL dimethylformamide was added dropwise. The mixture was stirred under argon for 24 hrs. The solvent was evaporated, the remaining oil was purified by chromatography on silica (Eluent Toluol/Aceticacidethylester 1:1). The fractions containing the product were collected and the solution was evaporated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]3[CH:23]=2)=[CH:10][CH:9]=1)=[O:6].Cl.[CH3:29][NH:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:29][N:30]([CH3:31])[C:26]1[CH:25]=[CH:24][C:4]([C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]4[CH:23]=3)=[CH:12][CH:13]=2)=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(F)c(F)c4)cc3)cn2c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(N(C)C)c(F)c4)cc3)cn2c1
Temperature: 100 °C
Yield: 61.8 %

Procedure:
A stirred mixture of 3,4-difluoro-N-[4-(6-methylimidazo[1,2-a]pyridin-2-yl)phenyl]benzamide (0.10 g, 0.275 mmol), dimethylamine hydrochloride (0.045 g, 0.551 mmol) and potassium carbonate (0.080 g, 0.577 mmol) in dry DMSO (3 ml) was heated at 100° C. for 18 h. After cooling to room temperature, the reaction mixture was added to water (100 ml) and the precipitate was collected by vacuum filtration, and washed with water (50 ml). The air-dried solid was then purified by flash chromatography (25:1 DCM/MeOH) to give the title compound (0.066 g, 62%) as a colourless solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:22])([F:21])[CH:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[O:9]1>C(OCC)C>[Cl:1][S:2]([C:18]1[CH:19]=[CH:20][C:10]2[O:9][CH:8]([C:7]([F:22])([F:21])[F:6])[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[CH:17]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)C1=Cc2ccccc2OC1C(F)(F)F
Solvent: CCOCC
Product: O=C(O)C1=Cc2cc(S(=O)(=O)Cl)ccc2OC1C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To chlorosulfonic acid (50.0 mL) chilled to −15° C. was added 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 10) (4.0 g, 16.7 mmol). After stirring at −15° C. for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. The resulting solution was added dropwise over ice (100 mL) with two diethyl ether(2×75 mL) extractions. The diethyl ether layers were combined, washed with water (2×75 mL), and brine (2×75 mL, dried over sodium sulfate and concentrated in vacuo. The resulting solids were triturated with hexane-ethyl acetate (9:1, 100 mL). The 6-chlorosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid was isolated as a white solid: mp 169–174. 1H NMR (CD3OD/300 MHz) 8.18 (d, 1H, J=2.7 Hz), 8.06 (dd, 1H, J=8.7, 2.7 Hz), 7.93 (s, 1H), 7.28 (d, 1H, J=8.7 Hz), 6.00 (q, 1H, J=6.6 Hz). EIHRMS m/z 324.9977 (M+, Calcd 324.9994).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[C:6](=O)([O:12]C(C)(C)C)[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][C@@H:2]([NH:1][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: C[C@H](N)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-aminopropan-1-ol (1 eq) in THF (0.3 M) at room temperature was added di-tert-butyl carbonate (1 eq) and triethylamine (1 eq). The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated en vaccuo; and the residue was diluted in ethyl acetate. The organic solution was washed with water (2×), 1:1 saturated aqueous NH4Cl, water and brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The material was carried onto the next step without further purification.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:6](=O)[CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10].CCOCC>C(Cl)(Cl)Cl>[Cl:1][C:9]1[NH:10][C:6]([C:5]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:3]([Cl:2])[CH:4]=2)=[CH:7][C:8]=1[C:11]#[N:12]
Reactant: Cl
Reactant: N#CC(C#N)CC(=O)c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)[nH]c1Cl
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 76 %

Procedure:
Hydrogen chloride gas is bubbled through a mixture of (3,4-dichlorophenacyl)malononitrile (8.3 g, 0.333 mol), ether (150 mL) and chloroform (100 mL) at a moderate rate, keeping the reaction mixture temperature below 35°-40° C. After 25 minutes, TLC shows the reaction is complete by UV analysis. The brown reaction mixture is poured into an ice-water mixture and extracted with ether. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a brown solid. The brown solid is washed with methylene chloride and filtered to give the title product as an off-white solid (6.7 g, 76%, mp >200° C.). Identified by IR and NMR spectral analyses.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([CH3:24])[CH:18]=1>>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[CH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:19]([CH3:24])[CH:18]=1
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Cc1cc(Cl)ccc1N
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(Cl)cc1C
Yield: 47.7 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.00 g, 24.1 mmol) and 4-chloro-2-methylaniline (5.13 g, 36.2 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (3.80 g, 48%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(=[O:20])C.[Na+]>C(O)(=O)C>[OH:17][CH2:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:20])[NH:7][N:6]=2)[CH2:9][CH2:10]1
Reactant: OCCCC1CCN(c2ccc(Cl)nn2)CC1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1ccc(N2CCC(CCCO)CC2)n[nH]1
Reaction time: 4 h

Procedure:
A mixture of 6 parts of 1-(6-chloro-3-pyridazinyl)-4-piperidinepropanol, 1.9 parts of sodium acetate and 150 parts of acetic acid was stirred for 4 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in 200 parts of a hydrochloric acid solution 10%. After stirring for 1 hour at reflux temperature, the whole was evaporated. The residue was taken up in water and treated with ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding a first fraction of 6-[4-(3-hydroxypropyl)-1-piperidinyl]-3(2H)-pyridazinone;
Reaction SMILES: C1(S(C2C=CC(Cl)=C([N+:16]([O-])=O)C=2)=O)C=CC=CC=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:22][C:21]=1[N+:40]([O-:42])=[O:41]>>[NH2:16][C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:22][C:21]=1[N+:40]([O-:42])=[O:41]
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccc(-c3ccccc3)cc2)ccc1Cl
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccccc2)ccc1Cl
Product: Nc1ccc(S(=O)c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]

Procedure:
The procedure described in Example 20 is followed, except that as a starting material instead of phenyl-(4-chloro-3-nitrophenyl) sulfoxide a corresponding amount of 4-(4-chloro-3-nitrophenyl-sulfinyl)-biphenyl is employed.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@H:21]2[CH2:29][O:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])(=[O:19])=[O:18])=[C:12]([CH3:39])[CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@H:21]2[CH2:29][O:30][CH2:31][C:32]([OH:34])=[O:33])(=[O:19])=[O:18])=[C:12]([CH3:39])[CH:11]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (1.5 ml) was added to a cooled (0° C.) solution of (S)-tert-butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)indolin-2-yl)methoxy)acetate (0.5 mmol) in DCM (6 ml) and the mixture was stirred for 2 h at room temperature. The solvent was removed under vacuum and the residue used in the subsequent stage.