Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][Cl:12])=[CH:6][CH:5]=1)=O.C(O)(=[O:15])C.BrBr.[S-:19][C:20]#[N:21].[K+]>C(OCC)(=O)C>[Cl:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[NH:21][C:20](=[O:15])[S:19][CH:1]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(CCCl)cc1
Reactant: N#C[S-]
Reactant: CC(=O)O
Agent: BrBr
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=c1[nH]c(-c2ccc(CCCl)cc2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a 125 ml round-bottomed flask equipped with N2 inlet were added 9.1 g (50 mmol) of 4-(2-chloroethyl)acetophenone and 25 ml acetic acid. To the stirred solution was added 2.58 ml (50 mmol) of bromine dropwise over 2 minutes. The reaction was stirred at room temperature for 30 minutes, taken up in ethyl acetate, washed with water, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated to an oil. The oil was taken up in 250 ml of acetone, treated with 4.9 g (50 mmol) of potassium thiocyanate, and stirred at room temperature for 3 hours. The precipitate was filtered and the filtrate evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to a solid. The solid was taken up in 100 ml of boiling ethanol and treated slowly with 83 ml of 1N HCl, then refluxed for 14 hours. The reaction was cooled and the precipitate filtered, washed with water, and dried to give 8.2 g (68%) of a white solid, m.p. 226°-229° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH:18]1([N:13]2[C:12]([C:37]3[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: FC(F)(F)c1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 67.3 %

Procedure:
The title compound (68 mg) was prepared as in Example 177, Steps C and D, using 130 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 132 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C20H24F3N3, 363.19; found, m/z 364.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.90-7.84 (m, 2H), 7.57-7.50 (m, 2H), 4.64 (br s, 2H), 3.94-3.85 (m, 1H), 3.33-3.05 (m, 4H), 2.93-2.72 (m, 2H), 2.00-1.76 (m, 6H), 1.67 (br s, 1H), 1.38-1.17 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8](COCCOC)[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][C:19]=3[CH2:30][N:31]3[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[C:32]3=[O:38])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C[Si](Cl)(C)C.[Na+].[I-].O>CC#N.CCOC(C)=O>[CH3:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][C:19]=3[CH2:30][N:31]3[CH2:35][CH2:34][C:33]([CH3:36])([CH3:37])[C:32]3=[O:38])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncccn2)cc1CN1CCC(C)(C)C1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1onc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncccn3)cc2CN2CCC(C)(C)C2=O)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)[1,1'-biphenyl]-2-sulfonamide in 5.1 ml of CH3CN, trimethylsilyl chloride ("Me3SiCl", 166 mg, 1.53 mmol) was added, followed by NaI (229 mg, 1.53 mmol). The mixture was stirred at room temperature for 1 hr. Additional Me3SiCl (166 mg, 1.53 mmol) and NaI (229 mg, 1.53 mmol) were added in three portions and the reaction was stirred for an additional 1 hr and 20 minutes. The reaction mixture was then added to 5 ml H2O and 30 ml EtOAc. The organic layer was separated and washed with 2 ml saturated aqueous sodium thiosulfate, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 32% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 68% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (29 mg, 21% for two steps) as a white solid, m.p. 125°-132° C. (amorphous).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[Cl-].[Li+].C(N(CC)CC)C.CS([Cl:42])(=O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a mixture of N-[4-(hydroxymethyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (2.20 g), lithium chloride (505 mg), triethylamine (1.67 ml), DMAP [4-dimethylaminopyridine] (catalytic amount) and dichloromethane (200 ml) was added methanesulfonyl chloride (645 μl), and the mixture was stirred at room temperature for 42 hours and concentrated under reduced pressure. To the residue was added 0.5N hydrochloric acid (200 ml), and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (973 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>CN(C)C=O>[CH3:18][C:19]1[N:20]([C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH:21]=[CH:22][N:23]=1
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1cnc(C(=O)O)cn1
Temperature: 100 °C

Procedure:
A mixture of methyl 5-chloropyrazine-2-carboxylate (0.75 g), K2CO3 (1.8 g) and 2-methyl-1H-imidazole (1.3 g) in N,N-dimethylformamide (6 mL) is heated to 100° C. overnight. Analysis of the crude mixture by LCMS shows saponified product. The solvents are evaporated and the crude product is purified by HPLC. LC (method 20): tR=0.27 min; Mass spectrum (APCI): m/z=205 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:8].C(N(CC)CC)C.[Cl:39][S:40]([C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46](Cl)=[O:47])(=[O:42])=[O:41]>ClCCl>[Cl:39][S:40]([C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46]([NH:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)=[CH:14][CH:15]=1)=[O:8])=[O:47])(=[O:42])=[O:41]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A mixture of 43.0 g of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 14.0 mL of triethylamine, and 215 mL of dichloromethane was added dropwise to a mixture of 24.8 g of 3-(chlorosulfonyl)benzoyl chloride and 430 mL of dichloromethane under ice-cooling, followed by stirring for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was washed with ethanol to obtain 59.5 g of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=O)[C:7]([OH:9])=[O:8])[CH:3]=[N:2]1.[OH-].[Mg+2].[OH-].[OH:14][NH:15]Cl>C(O)C.O>[OH:14][N:15]=[C:6]([C:4]1[CH:3]=[N:2][S:1][CH:5]=1)[C:7]([OH:9])=[O:8]
Reactant: ONCl
Reactant: O=C(O)C(=O)c1cnsc1
Agent: [Mg+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=NO)c1cnsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
A suspension of 2-(isothiazol-4-yl)glyoxylic acid (240 mg.), magnesium hydroxide (290 mg.) and hydroxylamino hydrochloride (140 mg.) in a mixture of ethanol (2 ml.) and water (10 ml.) was stirred for 2 hours at ambient temperature and allowed to stand overnight at ambient temperature. Ethanol was distilled off and to the residue was added ethyl acetate. The mixture was adjusted to pH 1 with 10% hydrochloric acid and the ethyl acetate layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 2-hydroxyimino-2-(isothiazol-4-yl)acetic acid (syn isomer) (0.20 g.), mp 159° to 161° C. (dec.).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]3[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=3)=[N:12][N:11]=2)=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:28][CH:29]=3)=[N:12][N:11]=2)=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCc3ccc(OCC(=O)OCC)cc3)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(CSc2nnc(SCc3ccc(OCC(=O)O)cc3)s2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 79.2 %

Procedure:
In 2 ml of 90% methanol was suspended 0.20 g of ethyl [p-[[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]methyl]phenoxy]acetate obtained in Example 26. Further 1 ml of a 1N aqueous sodium hydroxide solution was added to the suspension followed by stirring at room temperature for 1 minute. An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with a 1N hydrochloric acid and extracted with ethyl acetate. After the extract was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off. The resultant solids were recrystallized from isopropyl alcohol to give 0.15 g of [p-[[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]methyl]phenoxy]acetic acid.
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].[C:24](O)(=O)C>>[O:14]=[C:2]1[NH:3][C:4]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)/[C:1]/1=[CH:24]/[NH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]
Reactant: O=C1Cc2c(ccc3ncccc23)N1
Reactant: CC(=O)O
Reactant: N#Cc1cccc(N)c1
Product: N#Cc1cccc(N/C=C2\C(=O)Nc3ccc4ncccc4c32)c1
Yield: 78 %

Procedure:
Prepared from the dimethylaminomethylene derivative (Procedure E) of 1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one (Procedure C) with 3-aminobenzonitrile according to Procedure G in acetic acid to give the title compound in 78% yield as the acetate salt. 1H NMR (DMSO-d6) δ: 1.88 (s, 3H); 7.39 (d, J=8.5 Hz, 1H); 7.45-7.6 (m, 3H); 7.78 (m, 2H); 8.20 (s, 1H); 8.75 (d, J=4 Hz, 1H); 8.8-8.9 (m, 2H); 11.0 (s, 1H); 11.8 (d, J=12 Hz, 1H); 11.95 (s, 1H). ES-MS: m/z 313 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]([CH3:15])[S:11](Cl)(=[O:13])=[O:12].[CH3:16][O:17][C:18](=[O:31])[C@H:19]([C@@H:21]([CH3:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:31])[C@H:19]([C@@H:21]([CH3:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:20][S:11]([N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH3:15])(=[O:13])=[O:12]
Reactant: CN(CCc1ccccn1)S(=O)(=O)Cl
Reactant: COC(=O)[C@@H](N)[C@@H](C)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NS(=O)(=O)N(C)CCc1ccccn1)[C@@H](C)OCc1ccccc1

Procedure:
To the resulting compound from Example 87 (1 mmol) and (O-benzyl)threonine methyl ester (1 mmol) in CH2Cl2 was added triethylamine (2.0 mmol). After 1 h the product was isolated as described in Example 80.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:31](=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([O:21][CH3:31])=[CH:14][CH:13]=1)=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: COc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1C(N)=O

Procedure:
5-(N,N-Dibenzylglycyl)salicylamide (37.4 g) was heated at reflux for 2 hours with methyl iodide (10 ml) and anhydrous potassium carbonate (20 g) in ethyl methyl ketone (350 ml). The inorganic salts were filtered off and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and again evaporated. The residual oil was crystallised from isopropanol to give 5-(N,N-dibenzylglycyl)-o-anisamide as a white solid, (14 g) m.p. 113°-114° .
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([C:18]2[CH:26]=[CH:25][C:21]3OCO[C:20]=3[CH:19]=2)[CH:5]=1.COC(=O)C1C=C(OS(C(F)(F)[F:42])(=O)=O)C=C(OCC2C=CC=CC=2)C=1.FC1C=C(B(O)O)C=CC=1>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:18]2[CH:26]=[CH:25][CH:21]=[C:20]([F:42])[CH:19]=2)[CH:7]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)=[O:27]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccc3c(c2)OCO3)c1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: OB(O)c1cccc(F)c1
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2cccc(F)c2)c1

Procedure:
The title compound was prepared in the same way as 3-benzo[1,3]dioxol-5-yl-5-benzyloxy-benzoic acid methyl ester (described in Method B, step 3) from 3-benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester and 3-fluorophenylboronic acid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[F-].[K+].[C:15]([OH:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1C(=O)CCC1>[C:15]([O:23][C:11]1[CH:12]=[CH:2][CH:3]=[C:4]2[C:9]([O:8][C:6](=[O:7])[C:5]=12)=[O:10])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH:22][C:11]1[CH:12]=[CH:2][CH:3]=[C:4]2[C:9]([O:8][C:6](=[O:7])[C:5]=12)=[O:10]
Reactant: O=C(O)c1ccccc1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(Oc1cccc2c1C(=O)OC2=O)c1ccccc1
Product: O=C1OC(=O)c2c(O)cccc21

Procedure:
4-Fluorophthalic anhydride (0.44 g, 2.6 mmol shown as FPAN in table below), potassium fluoride (Aldrich, 0.14 g, 2.4 mmol), benzoic acid (Aldrich, 0.31 g, 2.5 mmol shown as BzOH in table below) and N-methyl pyrrolidinone (Aldrich, 3 ml) were heated in a 160° C. oil bath. The reaction was monitored by GC and showed the following results (BOPAN =benzoyloxyphthalic anhydride; ODPAN=oxydiphthalic anhydride; and HOPAN=hydroxyphthalic anhydride):
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-])=O)[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:20]=2[N:21]=1.C(O)(C(F)(F)F)=O>C(O)(C)C>[ClH:1].[CH3:12][C:8]1[CH:9]=[CH:10][C:11]2[C:2]([NH:26][C:23]3[CH:24]=[CH:25][C:19]4[S:18][C:17]([CH3:16])=[N:21][C:20]=4[CH:22]=3)=[N:3][CH:4]=[CH:5][C:6]=2[C:7]=1[NH2:13]
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Reactant: Cc1nc2cc(N)ccc2s1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(Nc3nccc4c(N)c(C)ccc34)ccc2s1
Product: Cl
Temperature: 25 °C
Yield: 91 %

Procedure:
Alternative preparation to Example 5: To a round bottom flask fitted with reflux condenser was added 1-chloro-6-methyl-5-nitroisoquinoline (13.0 g, 50 mmol), and 2-methyl-5-benzothiazolamine (8.63 g, 52.5 mmol). Nitrogen atmosphere was applied, and the mixture was treated with isopropanol (111 mL). The reaction vessel contents were stirred to obtain a slurry. TFA (11.35 mL, 150 mmol) was then added slowly and the contents of the flask were heated to reflux. The reaction was held at reflux for 17 h, then removed from heat. The reaction mixture was filtered on a fritted funnel at room temperature. The solid was reslurried in refluxing isopropanol (222 mL) for 18 h. The slurry was then cooled to room temperature and filtered. The resulting yellow solid was then dried under vacuum at 55° C. overnight to 17.77 g 6-methyl-N1-(2-methylbenzo[d]thiazol-5-yl)isoquinoline-1,5-diamine hydrochloride (91% yield). MS (M+H)+ 351.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(=CC#N)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:31]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]3)=[O:20])=[CH:14][CH:13]=2)[CH:18]=[C:10]1[C:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]1)=[O:9])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OCc1ccccc1
Agent: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3Cc2ccccc2)CC1
Reaction time: 3 h
Yield: 60.1 %

Procedure:
The suspension of 0.15 g (0.36 mmol) (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 72 μL (76 mg, 0.72 mmol) benzylalcohol and 173 mg (0.72 mmol) (triphenylphosphoranylidene)acetonitrile in 2 mL toluene was stirred for 3 hours under reflux. The volatile components were evaporated at a rotary evaporator and the residue was purified using flash chromatography on silica gel with dichloromethane:methanol (19:1 v/v) as eluant to give 0.11 g (63%) of the desired compound as a light brown foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]([CH3:39])=[C:33]([CH2:35][CH2:36][CH2:37]O)[N:34]=2)=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:37][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[O:31][C:32]=2[CH3:39])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Reactant: COc1ccc(-c2nc(CCCO)c(C)o2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCCc2nc(-c3ccc(OC)cc3)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 108 b]) was reacted with 3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propanol (example 42 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid as colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]3)[NH:9][CH2:8][CH2:7][C:6]2=1.C([N:44]1[CH:48]=[C:47]([C:49](O)=[O:50])[N:46]=[CH:45]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][CH2:18][CH2:19]3)[N:9]([C:49]([C:47]3[NH:46][CH:45]=[N:44][CH:48]=3)=[O:50])[CH2:8][CH2:7][C:6]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C2c3[nH]c4ccc(Cl)cc4c3CCN2C(=O)c2cnc[nH]2)CCC1

Procedure:
1.84 g of the compound of Example 1, 1.8 g of N-tritylimidazole-4-carboxylic acid, 1.92 ml of diisopropylethylamine and 1.76 g of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate are stirred at ambient temperature for 24 hours. After dilution with 500 ml of water, filtration, and extraction with dichloromethane, the organic phases are dried and filtered and then concentrated under reduced pressure. Crystallisation of the residue in an ethanol-diethyl ether-hydrogen chloride mixture enables the expected compound to be isolated.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>ClCCl>[CH3:9][C:6]1([CH3:10])[O:5][C@@H:4]([CH2:3][CH2:2][O:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:8][O:7]1
Reactant: CC1(C)OC[C@H](CCO)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@H](CCOS(C)(=O)=O)O1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101 %

Procedure:
To a solution of (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich) (21.1 g, 0.14 mol) and triethylamine (40 mL, 0.28 mol) in dichloromethane (250 mL) at 0° C. was added methanesulfonyl chloride (13.4 mL, 0.17 mol) dropwise. The reaction mixture was stirred at 0° C. for 1.5 h, then water was added. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester as a yellow oil (31.7 g, 98%).