Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][C:14]1[CH:13]=[N:12][N:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:27])=[O:2])[C:16](=[O:17])[CH:15]=1)#[N:26]
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2C#N)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
A solution of 2-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (30 g, 82 mmol) in methanol (30 mL) was treated with a 4N aqueous sodium hydroxide solution (26.5 mL, 106 mmol) and stirred at 25° C. for 18 h. At this point, the reaction was concentrated in vacuo and then diluted with water. The translucent aqueous solution was acidified to pH 4-5 with a 1N aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration, rinsed and dried in vacuo to afford 2-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (12.0 g, 41%) as a white solid; ESI-MS 354 [M+H+]; HPLC: >96% (purity). 1H-NMR (300 MHz, CDCl3) δ 9.65 (s, 1H), 7.93 (s, 1H), 7.68-7.78 (m, 2H), 7.43-7.45 (m, 1H), 7.28-7.31 (m, 1H), 6.07 (s, 1H), 5.51-5.56 (m, 1H), 2.29-2.39 (m, 1H), 2.05-2.15 (m, 1H), 1.44-1.82 (m, 7H), 1.09-1.22 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([S:8]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][CH2:18]O)[N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([S:8]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][CH2:18][Cl:41])[N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCCl)cs1

Procedure:
A mixture of EXAMPLE 181A (100 mg, 0.30 mmol), triphenylphosphine (158 mg, 0.60 mmol) and carbontetrachloride (116 mg, 0.75 mmol) in DMF (2 mL) was stirred over night, and was then poured into water. The mixture was extracted with EtOAc, dried (Sodium sulfate) and the solvent was evaporated. The crude material was purified by flash chromatography on silica gel gradient eluting with 2-4% acetone in DCM giving a solid (25 mg, 24%). 1H NMR (CDCl3) δ 2.64 (s, 3H), 3.17 (t, 2H), 3.77 (t, 2H), 6.30 (s, 1H), 7.24 (m, 2H), 7.56 (d, 1H), 8.02 (d, 1H); MS (Ionspray, [M+H]+) m/z 350.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([C:13](O)=[O:14])=[CH:7][CH:6]=2)[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH2:50]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH:50][C:13]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:3]([CH2:1][CH3:2])=[C:11]2[CH3:12])=[O:14]
Reactant: CN(C)CCN
Reactant: CCc1c(C)c2cc(C(=O)O)ccc2n1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1c(C)c2cc(C(=O)NCCN(C)C)ccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 mg portion of 2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxylic acid, 231 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 54 mg of 1-hydroxybenzotriazole were dissolved in 8 ml of N,N-dimethylformamide, and then 106 mg of N,N-dimethyl-1,2-ethanediamine was added, followed by overnight stirring at room temperature. The reaction liquid was diluted with chloroform and then washed with a 1 M sodium hydroxide aqueous solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=100:1:0.1 to 50:1:0.1 to 30:1:0.1) to obtain 257 mg of N-[2-(dimethylamino)ethyl]-2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxamide as a colorless oily material. This product was dissolved in 2.5 ml of acetonitrile at 80° C., and 67 mg of oxalic acid was added, followed by stirring at 80° C. for 10 minutes and then stirring at room temperature for 2 hours. The resulting solid was collected by filtration and then washed with acetonitrile to obtain 236 mg of N-[2-(dimethylamino)ethyl]-2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxamide oxalate as a pale purple solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)=[CH:4][C:3]=1[OH:24].[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>CC(N(C)C)=O>[OH:24][C:3]1[CH:4]=[C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH:22]=[CH:23][C:2]=1[NH:1][C:25](=[O:28])[CH:26]=[CH2:27]
Reactant: Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reactant: C=CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: C=CC(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 142.2 %

Procedure:
A solution of (4Z)-4-{[(4-amino-3-hydroxybenzyl)amino]methylene}-6-iodoisoquinoline-1,3(2H,4H)-dione (1.1 g, 2.3 mmol) in dimethylacetamide (12 mL) is cooled to 0° C. in an ice water bath. Acryloyl chloride (1.9 mL, 23 mmol) is added and the mixture is stirred at 0° C. for 15 minutes. The reaction mixture is then concentrated under reduced pressure and combined with impure material from a previous batch. The material is adsorbed onto flash silica gel, which is then subjected to flash chromatography (methanol/chloroform) to give N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]acrylamide (1.6 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2=[O:20].[OH:21]P([O-])([O-])=O.[K+].[K+].OP([O-])(O)=O.[K+]>CS(C)=O.O>[CH:2]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2=[O:20])=[O:21]
Reactant: CCOC(=O)CCN1C(=O)c2ccc(CBr)cc2C1=O
Reactant: O=P([O-])([O-])O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCN1C(=O)c2ccc(C=O)cc2C1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The crude material from step 2 was dissolved in DMSO (70 mL). Powdered K2HPO4 (18 g, 0.10 mol) and KH2PO4 (7 g, 0.05 mol) were added. The mixture was stirred at 80° C. for 5 hours, diluted with water (500 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (MgSO4), and concentrated. After column chromatography (hexane, ethyl acetate 3:1) 4.8 g of the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:22](=[O:24])[CH3:23])[CH2:11][C:12]2[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].O>O1CCCC1>[OH:24][CH:22]([CH3:23])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:11][C:12]1[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(CC(C(C)=O)c2ccc([N+](=O)[O-])cc2)o1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)O)o1
Temperature: -78 °C
Yield: 66.4 %

Procedure:
5.48 g of ethyl 5-{2-(4-nitrophenyl)-3-oxobutyl}-2-furancarboxylate in 50 ml of tetrahydrofuran was mixed with 16.5 ml of 1M lithium tri-sec-butylborohydride in tetrahydrofuran under cooling at -78° C. under stirring and stirred at the same temperature for 2 hours. After addition of water, the reaction solution was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1→1/1] to give 3.66 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1>CN(C)C=O>[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[CH:12][CH:11]=1
Reactant: BrCc1ccc(I)cc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 2-pyrrolidinone (850 mg, 10 mmol) in dimethylformamide (40 ml) was cooled in an ice/methanol bath with stirring under an atmosphere of argon. Then a solid suspension of sodium hydride (60% in mineral oil, 440 mg, 11 mmol) was added portionwise over 10 minutes. The reaction mix was allowed to stir with cooling for 30 minutes, then 4-iodobenzyl bromide (2.97 g, 10 mmol) was added portionwise over 10 minutes. The whole mix was allowed to warm slowly up to room temperature then stirred for a further 2 hours. The reaction mixture was partitioned between ethyl acetate (100 ml), and water (200 ml), the organic layer was removed and reduced to minimum volume under reduced pressure. The residue was purified by column chromatography on a 20 g pre-packed silica column eluting from 0-100% ethyl acetate in petroleum ether to give the title compound as a yellow solid (2.97 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=O.[C:14]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=[O:15]>C1(C)C=CC=CC=1>[CH2:10]([C:4]1[N:5]=[C:6]([CH2:8][CH3:9])[CH:7]=[C:2]2[C:3]=1[CH:12]=[CH:17][C:14](=[O:15])[NH:1]2)[CH3:11]
Reactant: CCc1cc(N)c(C=O)c(CC)n1
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCc1cc2[nH]c(=O)ccc2c(CC)n1
Yield: 76.2 %

Procedure:
A mixture of 4-amino-2,6-diethylpyridine-3-carbaldehyde (40 g) and (carboxymethylene)triphenylphosphorane (82.5 g) in toluene (1 l) was stirred and heated at reflux for 3 hours. The solution was cooled and the solvent was removed by evaporation. A solution of sodium (20 g) in methanol (800 ml) was added to the residue and the resulting solution was heated at reflux for 4 hours. Methanol was removed by evaporation and water (500 ml) was added. The mixture was acidified to pH 1-2 by addition of concentrated hydrochloric acid. The mixture was then extracted with ethyl acetate (2×500 ml) and ether (1×500) and the extracts were discarded. The aqueous phase was then basified by addition of solid potassium carbonate and the solid which crystallised was collected by filtration and washed with water. The solid was recrystallised from acetone to give 5,7-diethyl-1,6-naphthyridin-2(1H)-one (34.6 g), m.p. 168°-169° C.; NMR (d6 -DMSO): 1.24(dt, 6H), 2.72(q, 2H), 3.0(q,2H), 6.46(d, 1H), 6.9(s, 1H), 8.07(d, 1H); mass spectrum (CI: 203 (M+H)+ ; microanalysis, found: C, 70.9; H, 6.9; N, 13.8%; C12H14N2O requires: C, 71.3; H, 6.98; N, 13.9%.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Br[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(Cl)Cl>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][NH:4][CH:1]1[CH2:3][CH2:2]1)[CH3:11]
Reactant: CCOC(=O)CBr
Reactant: NC1CC1
Solvent: ClCCl
Product: CCOC(=O)CNC1CC1
Temperature: 25 °C

Procedure:
Cyclopropylamine (12.1 mL, 175 mmol) and TEA (42 mL, 385 mmol) were combined at 0° C. in 350 mL CH2Cl2, then ethyl bromoacetate (19.4 mL, 175 mmol) was added dropwise. The reaction was warmed to RT for 3 h, then diluted with additional CH2Cl2, washed with water, sat. NaHCO3, and brine, dried (Na2SO4), filtered and concentrated. Flash filtration (silica, 30% EtOAc/hexane) provided 7-2 as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:56]([C:58]1[C:59]([C:64](O)=[O:65])=[N:60][CH:61]=[CH:62][CH:63]=1)[CH3:57]>CC(N(C)C)=O>[CH2:56]([C:58]1[C:59]([C:64]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:65])=[N:60][CH:61]=[CH:62][CH:63]=1)[CH3:57]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CCc1cccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCc1cccnc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 69.1 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (100 mg, 0.315 mmol) obtained in Example 1, (3), HATU (180 mg, 0.473 mmol), triethylamine (132 μL, 0.945 mmol), and 3-ethylpicolinic acid (71 mg, 0.473 mmol) were stirred at room temperature for 2 hours in anhydrous dimethylacetamide (10 mL). The reaction mixture was post-treated in a conventional manner to give the title compound (98 mg, yield 69%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:4][NH:5][C:6](=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:3].[CH2:13]([O:17][C:18](Cl)=[O:19])[CH:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH2:13]([O:17][C:18]([N:5]([C:6](=[O:11])[CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:4][C:2]([CH3:1])([CH3:12])[NH2:3])=[O:19])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)CC(=O)NCC(C)(C)N
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)N(CC(C)(C)N)C(=O)CC(C)C

Procedure:
Using the same conditions as in Example 7, 5.1 parts of 2,2,7,7 -tetramethyl-1,4-diazaheptan-5-one, 30 parts of isobutylchloroformate and 150 parts of anhydrous toluene afforded 4-isobutoxycarbonyl-2,2,7,7-tetramethyl-1,4-diazaheptan-5-one of boiling point 134°C at 0.8mm pressure. The hydrochloric acid salt of this material showed a melting point of 179° -181°C and gave the following elemental analysis by weight:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:40]=[CH:39][C:35]2[O:36][CH2:37][O:38][C:34]=2[CH:33]=1>>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([CH2:31][O:1][C:2]3[CH:3]=[C:4]([C:8]4[C:17]5[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=5)[N:11]=[CH:10][C:9]=4[C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:23])[CH:5]=[CH:6][CH:7]=3)=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: BrCc1ccc2c(c1)OCO2
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc3c(c2)OCO3)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 5-Bromomethyl-benzo[1,3]dioxole following the procedure of Example 478: MS (ESI) m/z 528; HRMS: calcd for C31H20F3NO4+H+, 528.14172; found (ESI, [M+H]+), 528.1435.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.[F:24][C:25]1[CH:30]=[C:29](F)[N:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:20]([NH:23][C:29]2[CH:30]=[C:25]([F:24])[N:26]=[CH:27][N:28]=2)(=[O:21])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1
Reactant: Fc1cc(F)ncn1
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(N)(=O)=O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2cc(F)ncn2)cc1F
Yield: 61.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 16d by using the 3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (0.07 g, 0.21 mmol) prepared in Example 16c, 4,6-difluoropyrimidine (0.07 g, 0.62 mmol), potassium carbonate (0.11 g, 0.83 mmol) and DMF (2.0 mL), to yield the title compound (56 mg, 63%) as a colorless solid.
Reaction SMILES: [C:1]1([SH:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl[CH2:10][C:11]([C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O>>[S:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[S:8][CH:10]=[C:11]1[C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: Sc1ccccc1S
Product: CCOC(=O)C(=NOC)C1=CSc2ccccc2S1
Yield: 6.8 %

Procedure:
o-Benzenedithiol (7.1 g.) was allowed to react with ethyl 2-chloroacetyl-2-methoxyiminoacetate (11.4 g.) in a similar manner to that of Example A--(i) to give ethyl 2-(1,4-benzodithiin-2-yl)-2-methoxyiminoacetate (syn isomer, 1.0 g.), yellow crystals, mp. 78° to 81° C.
Reaction SMILES: [C:1]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7]Cl)=[O:5].[O:15]1[CH2:20][CH2:19][O:18][C:17]2[CH:21]=[C:22]([C:25]3[C:29]4[O:30][C:31]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:32][C:33](=[O:34])[C:28]=4[S:27][CH:26]=3)[CH:23]=[CH:24][C:16]1=2.[I-:41].[Na+]>C(#N)C>[I-:41].[C:11]([O:10][C:1](=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][O:34][C:33]1[CH:32]=[C:31]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[O+:30]=[C:29]2[C:25]([C:22]3[CH:23]=[CH:24][C:16]4[O:15][CH2:20][CH2:19][O:18][C:17]=4[CH:21]=3)=[CH:26][S:27][C:28]=12)=[O:5])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CCC(=O)OCCl
Reactant: O=c1cc(N2CCOCC2)oc2c(-c3ccc4c(c3)OCCO4)csc12
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCC(=O)OCOc1cc(N2CCOCC2)[o+]c2c(-c3ccc4c(c3)OCCO4)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A 10 mL vial was charged with a magnetic stirring bar, tert-butyl chloromethyl succinate (24 mg, 0.107 mmol), acetonitrile (2 mL), 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-morpholino-7H-thieno[3,2-b]pyran-7-one (28) (20 mg, 0.054 mmol) and sodium iodide (12 mg, 0.081 mmol). The reaction mixture was magnetically stirred for 18 hours at 70° C. to give 7-((4-tert-butoxy-4-oxobutanoyloxy)methoxy)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-morpholinothieno[3,2-b]pyran-4-ium iodide (81).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: OCC1Cc2cc(C(F)(F)F)cc(Br)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(Br)c3O2)cc1
Yield: 70 %

Procedure:
Treatment of (±)-[7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (3.59 g, 12.1 mmol) with p-toluenesulfonyl chloride (3.6 g, 18.2 mmol) generally according to described for Intermediate 10 provided 3.82 g (70%) (±)-[7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. mp 95-97° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[O:4][CH2:5][C@H:6]([NH:8]C(OC(C)(C)C)=O)[CH3:7].[ClH:18]>CCOC(C)=O.O1CCOCC1>[ClH:18].[CH3:1][N:2]([CH3:17])[C:3](=[O:16])[O:4][CH2:5][C@H:6]([NH2:8])[CH3:7]
Reactant: C[C@H](COC(=O)N(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](N)COC(=O)N(C)C
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-[(tert-Butoxycarbonyl)amino]propyl dimethylcarbamate (16.0 mg, 0.0650 mmol) in EtOAc (0.2 mL) was added 4M of hydrogen chloride in 1,4-dioxane (0.5 mL) and stirred for 1 h. The volatiles were removed under reduce pressure to give the desired compound. LCMS: (M+H)=147.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>CS(C)=O.CCOCC>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)=[CH:23][CH:22]=1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Reactant: Fc1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCN(CC)CCCCOc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
260 mg (1 mmol) Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine in 2 ml DMSO were treated with 175 mg (1 mmol) 1-bromo-4-fluorobenzene and 26.4 mg (0.1 mmol) 18-crown-6 and 182 mg (1 mmol) KF on alox. The suspension was stirred at 120° C. for 2 h, additional 175 mg (1 mmol) 1-bromo-4-fluorobenzene, 26.4 mg (0.1 mmol) 18-crown-6 and 182 mg (1 mmol) KF on alox were added. The suspension was stirred for 1 h, cooled to RT and diluted with ether and filtered. The solution was washed with 1M NaOH and water, and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 4:1 yielded 205 mg (48%) {4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine as light yellow oil, MS: 415 (MH+, 1Br). (analogously to William J. Smith III, J. Scott Sawyer, Tetrahedron Letters 1999, Vol.37, No.3, 299-302.)
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>O>[N:16]1([S:2]([C:5]2[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCCC2)cc1C(=O)O
Reaction time: 6 h

Procedure:
5-Chlorosulphonyl-2-methoxybenzoic acid (4.9 g) was added to a solution of pyrrolidine (10 g) in water (150 ml). The solution was stirred for 6 hours, filtered and acidified with dilute hydrochloric acid to yield the title compound as colourless microcrystals (5.27 g; 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24].[S:25]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])(=[O:27])[NH2:26]>>[S:25]([C:29]1[CH:30]=[C:31]([NH:35][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:32]=[CH:33][CH:34]=1)(=[O:27])(=[O:28])[NH2:26]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.6) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 510.2 [(M+H)+]; mp 275° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(OCC)(=O)C>C(Cl)Cl>[CH2:9]([O:8][C:6]([NH:4][CH2:3][CH2:1][OH:2])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To ethanolamine (9.0 ml, 149 mmol) in methylene chloride (100 ml) at 0° C. was added benzyl chlorformate (10.0 ml, 70 mmol). The mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2M HCl, saturated NaHCO3 solution, and brine, then dried over Na2SO4 and evaporated to provide 12.91 g (94%) of the desired compound as a white solid. 1H-NMR (CDCl3,TMS) 7.47 (m,5H), 5.11 (s,2H), 3.73 (m,2H), 3.38 (m,2H).