Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][C:7]1([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:21]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]2[C:32]([CH2:33]Cl)=[CH:31][N:30]=[CH:29]2)=[CH:25][CH:24]=1)#[N:22].C(N(C(C)C)CC)(C)C>C(#N)C>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:28]2[C:32]([CH2:33][N:10]3[CH2:9][CH2:8][C:7]([CH2:6][C:5]4[CH:17]=[CH:18][CH:19]=[C:3]([CH3:2])[CH:4]=4)([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11]3)=[CH:31][N:30]=[CH:29]2)=[CH:35][CH:36]=1)#[N:22]
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: COC(=O)C1(Cc2cccc(C)c2)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C1(Cc2cccc(C)c2)CCN(Cc2cncn2Cc2ccc(C#N)cc2)CC1

Procedure:
A solution of methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt (142 mg, 0.5 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (135 mg, 0.5 mmol; Example 52, Step D), and diisopropylethylamine (0.26 mL, 1.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform. After collection and concentration of appropriate fractions, the residue was recrystallized from a mixture of ethyl acetate and hexane to provide the title compound as white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:41]=2[C:42](O)=[O:43])=[CH:34][CH:33]=1>CN(C)C=O.O>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]([F:50])([F:51])[F:52])=[CH:45][C:41]=2[C:42]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[O:43])=[CH:34][CH:33]=1
Reactant: Nc1ccnnc1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Nc1ccnnc1)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Pyridazinamine (60.5 mg, 0.64 mmol), EDC (122 mg, 0.64 mmol), HOBT (63.4 mg, 0.41 mmol) and diisopropylethylamine (0.11 ml, 0.64 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 119; 100 mg, 0.32 mmol) in N,N-dimethylformamide (20 ml) and the mixture was stirred at room temperature overnight. The mixture was then heated to 70° C. overnight (NOTE: it would be better to prepare the acid chloride and react this with the amine). The mixture was diluted with water (25 ml) and extracted with ethyl acetate (3×25 ml). The organics were combined, evaporated under reduced pressure on a buchi and the residue was purified using an MDAP to yield the title compound. 70 mg.
Reaction SMILES: [N+]([O-])(O)=O.[Cl:5][C:6]1[C:7]([F:16])=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([OH:11])=[O:10].[Br:17]Br>C(O)(=O)C.O.[N+]([O-])([O-])=O.[Ag+]>[Br:17][C:13]1[C:14]([F:15])=[C:6]([Cl:5])[C:7]([F:16])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C(O)c1cc(Br)c(F)c(Cl)c1F
Reaction time: 14 h

Procedure:
In a mixture of 50 ml of acetic acid, 10 ml of water and 13 ml of nitric acid is dissolved 2 g (0.014 mole) of 3-chloro-2,4-difluorobenzoic acid and 3.64 ml (0.028 mole) of bromine. A solution of 3.52 g (0.0208 mole) of silver nitrate in 10 ml of water is then added slowly. After 14 hours at 20° C., the precipitate is filtered and rinsed with ether. The organic phase is washed with sodium bisulfite, then water and dried. Removal of the solvent affords the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][S:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][S:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:33])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: COC(=O)CS(=O)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Methyl ({[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl}thio)acetate (0.10 g, 0.28 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.064 g, 0.28 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.096 g, 92%) as pale yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([O:10][CH3:11])=[C:7]([F:9])[CH:8]=1.[C-:20]#[N:21].[K+]>CN(C=O)C>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][C:20]#[N:21])[CH:4]=[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[O:10][CH3:11]
Reactant: COc1c(F)cc(CCl)cc1OCc1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(F)cc(CC#N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
5-(Chloromethyl)-1-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]benzene (2.88 g, 10.26 mmol.) was taken into DMF (15 mL) followed by addition of potassium cyanide (1.0 g, 15.4 mmol.) and the resulting mixture was allowed to stir at room temperature over 12 hours. The mixture was then partitioned with ethyl ether and water and the organic phase washed with water (3×) then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Filtration and concentration gave {3-fluoro-4-(methyloxy)-5-[(phenylmethyl)oxy]phenyl}acetonitrile (2.69 g, 97% yield) as a clear oil. GCMS for C16H14O2FN: 271 (M+).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N+:23]([O-])=O)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]3[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:29]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(Br)cc(c23)C(=O)N1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(Br)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)C1
Yield: 80.8 %

Procedure:
Following the procedure of Example W1, 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (0.40 g, 0.94 mmol, from Example S1-A), (S)-pyrrolidin-3-yl-carbamic acid, tert-butyl ester (0.38 g, 2.1 mmol) and triethyl amine (0.18 g, 1.9 mmol) in DMF (5 mL) were reacted at 80° C. for 48 hours to give 0.43 g of the title compound.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:13]([CH3:34])[O:12][C@H:11]1[O:35][C@@H:36]1[C@H:45]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:44]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@H:43]([CH3:62])[O:42][C@H:37]1[O:38]CC=C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[C:1]([O:9][C@@H:10]1[C@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:13]([CH3:34])[O:12][C@H:11]1[O:35][C@@H:36]1[C@H:45]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@@H:44]([O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C@H:43]([CH3:62])[O:42][C@H:37]1[OH:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1O[C@@H]1O[C@@H](C)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@H]1O[C@@H](O)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
1,5-Cyclooctadiene-bis(methyldiphenylphosphine)iridium hexafluorophosphate (25 mg) was dissolved in THF (10 mL) and the resulting red solution was degassed in an argon stream. Hydrogen was then bubbled through the solution, until the colour had changed to yellow. The solution was then degassed again in an argon stream. A solution of 528 (4.71 g, 5.59 mmol) in THF (40 mL) was degassed and added. The mixture was stirred at rt overnight, then concentrated. The residue was taken up in acetone (350 mL) and water (82 mL). Mercuric bromide (3.23 g, 8.96 mmol) and mercuric oxide (2.64 g, 12.3 mmol) were added to the mixture, which was protected from light. The suspension was stirred at rt for 1 h, then concentrated. The residue was taken up in CH2Cl2 and washed three times with sat aq KI, then with brine. The organic phase was dried and concentrated. The residue was purified by column chromatography (solvent B, 3:1) to give 529 (3.87 g, 84%) as a colourless foam. 1H NMR: δ 8.15-7.12 (m, 25H, Ph), 5.94-5.88 (m, 3H, H-2A, 3A, CH═), 5.70 (pt, 1H, J3,4=9.7 Hz, H-4A), 5.31 (dd, 1H, J1,OH=3.0 Hz, H-1B), 5.28 (bs, 1H, H-1A), 4.98 (d, 1H, J=11.0 Hz, CH2Ph), 4.82-4.68 (m, 3H, CH2Ph), 4.31 (dq, 1H, J4,5=9.8 Hz, H-5A), 4.13 (dd, 1H, J1,2=2.1 Hz, H-2B), 4.06-3.99 (m, 2H, H-3B, 5B), 3.72 (pt, 1H, J3,4=J4,5=9.4 Hz, H-4B), 2.79 (bs, 1H, OH-1B), 1.41 (d, 3H, J5,6=6.2 Hz, H-6B), 1.37 (d, 3H, J5,6=6.3 Hz, H-6A); 13C NMR: δ 166.2, 165.9, 165.7 (3C, C═O), 138.9-127.9 (Ph), 99.7 (C-1A), 94.2 (C-1B), 80.5 (C-4B), 79.6 (C-3B), 77.6 (C-2B), 76.5, 72.5 (2C, CH2Ph), 72.3 (C-4A), 71.0 (C-2A*), 70.4 (C-3A*), 68.8 (C-5B), 67.6 (C-5A), 18.5 (C-6B*), 18.1 (C-6A*). FAB-MS for C47H46O12 (M, 802.3) m/z 825.1 [M+Na]+. Anal. Calcd. for C47H46O12.0.5H2O: C, 69.53; H, 5.84%. Found C, 69.55; H, 5.76%.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].CO.O.NN>CCCCCC>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([NH2:12])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N)c([N+](=O)[O-])c1
Agent: NN
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CCCCc1ccc(N)c(N)c1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
1.11 g (5.15 mM) of 4-butyl-2-nitroaniline, 5 ml of methanol, 0.35 g of activated carbon and 0.04 gof ferric chloride hexahydrate were placed in a 50 ml-three-neckedflask and kept at about 60° C. To themixture, 1.5 ml (24.7 mM) of hydrazine hydrate wasgradually added dropwise, followed by stirring for 2 hours under heat refluxing. After the reaction, thereaction mixture was subjected to filtration by meansof suction under heating to remove the activatedcarbon. The filtrate was concentrated under reducedpressure and an appropriate amount of water was addedthereto. The mixture was subjected to extraction withethyl acetate. The organic layer was washed withwater and dried with milabilite, followed byconcentration under reduced pressure to obtain a crudeproduct. To the crude product (residue), anappropriate amount of hexane was added, followed bycooling on an ice bath to precipitate a crystal. Thecrystal was recovered by filtration to obtain 0.82 gof 4-butyl-1,2-phenylenediamine (Yield: 87.4%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1)=[O:15]
Reactant: Nc1nc2[nH]ccc2c(=O)[nH]1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1nc2[nH]ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (186 g, 1.23 mol) in pyridine (2 L) was treated with trimethylacetyl chloride (475 g, 3.94 mol, 485 mL, 3.2 eq) at 90° C. for 2 h, to give a mixture of N(2)-monoacylated and N(2), N(7)-bisacylated material. The solvent was evaporated and the residue was taken up in aqueous ammonia (37% NH3, 310 mL) and MeOH (2 L), and stirred at rt for 30 min, to selectively cleave the N(7)-pivaloyl group. The solid was collected by filtration, washed with water (500 mL×5), and dried on high vacuum to give the title compound as a solid (193 g). Concentration of the mother liquor provided additional solid material, which was collected, washed with water (50 mL×5), and dried (77 g). The combined yield was 93% (HPLC purity 98.6%). tR: 4.57 min. 1H-NMR (DMSO-d6) δ 12.00, (br. s, 1H), 7.40 (br. s, 1H), 6.96 (q, 1H), 6.40 (q, 1H), 1.24 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[N:10][N:6]2[C:7](=[O:9])[CH:8]=1.[C:13]([O-:16])(=[O:15])[CH3:14].[K+]>CN(C)C=O>[C:13]([O:16][CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[N:10][N:6]2[C:7](=[O:9])[CH:8]=1)(=[O:15])[CH3:14]
Reactant: O=c1cc(CCl)nc2scnn12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(=O)n2ncsc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
7-chloromethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one (10 g), prepared according to Example 1, was dissolved in dimethylformamide (40 ml) and reacted with anhydrous potassium acetate (10 g) under stirring at room temperature for 20 hours. After dilution with ice water the precipitate was filtered and washed with water to give 7-acetoxymethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one (9.7 g) which was hydrolyzed by treatment with 37% HCl (50 ml) in dioxane (100 ml) under stirring at room temperature for 2 hours. The reaction mixture was diluted with acetone and the precipitate was filtered and then treated with aqueous Na2HPO4 : filtration and washings with water until neutral gave 7-hydroxymethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one (6.2 g) which was reacted with dicyclohexylcarbodiimide (14.4 g) in benzene (90 ml) and dimethylsulphoxide (25 ml) in the presence of trifluoroacetic acid (1 ml) and pyridine (1.71 ml) under stirring at room temperature for 20 hours. After treatment with oxalic acid bihydrate (3.1 g) at room temperature, the precipitate of dicyclohexylurea was filtered of and the organic solution was evaporated in vacuo to dryness: the residue was purified over a SiO2 column using chloroform: ethyl acetate=95:5 as eluent. The 7-formyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one so obtained (2.5 g) was reacted with the ylide obtained by treatment of triphenylphosphonium-benzyl chloride (2.94 g) with 50% NaH (0.43 g), in dimethylsulphoxide (40 ml) at room temperature for 22 hours. After dilution with ice water the precipitate was filtered and washed with water: crystallization from CH2Cl2 -ethanol gave 2.1 g of 7-trans-(2-phenyl-ethenyl)-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 216°-218° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.CN1CCOCC1.[C:20]([O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)([CH3:23])([CH3:22])[CH3:21].O>CN(C)C=O>[C:20]([O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])=[CH:31][CH:32]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Cc1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 11.7 %

Procedure:
A solution of indole-6-carboxylic acid (2.00 g, 12.40 mmol) in dimethylformamide (20.00 mL) under argon was treated with N-methyl morpholine (6.82 mL, 62.04 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexaflurophophate (HATU) (7.08 g, 18.62 mmol) and (4-amino-phenyl)-acetic acid tert-butyl ester (2.57 g, 12.40 mmol). The mixture was warmed at 60° C. and stirred for 18 hours. After cooling to room temperature, water (15.00 mL) was added. The resulting slurry was extracted with ethyl acetate and the combined organic phases washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), to yield pure {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester (0.51 g) and a mixture of {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester and 1H-indole-6-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (3.41 g). This was dissolved in tetrahydrofuran (34.00 mL) and treated with 1N NaOH. The mixture was stirred at room temperature for 4 hours, then extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulphate and evaporated, and the residue triturated in ether to afford {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester (1.36 g), which was combined with the aliquot obtained by flash chromatography. Total yield of {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester, 1.87 g (43%), MS (mass spectrometry) (ISP): m/e=351.3 (M+H). As used herein (M+H)=the molecular weight of the compound plus a proton.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.CS(O[CH2:22][CH:23]([Cl:25])[Cl:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][CH2:22][CH:23]([Cl:25])[Cl:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CS(=O)(=O)OCC(Cl)Cl
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(OCC(Cl)Cl)c2CC[C@@H]1C
Temperature: 110 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
A 40-mL resealable tube was charged with 1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (90 mg, 0.32 mmol), 2,2-dichloroethyl methanesulfonate (82 mg, 0.42 mmol), potassium carbonate (135 mg, 0.96 mmol), and N,N-dimethylformamide (10 mL). The resulting mixture stirred for 48 h at 110° C. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluting with petroleum ether/ethyl acetate, 10:1 then 1:2) to afford 1-[(2S)-6-bromo-5-(2,2-dichloro ethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (56 mg, 46%) as light yellow oil. MS (ESI, pos. ion) m/z 31, 383 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC=CC=1.C([Li])(C)(C)C.CN(C)[CH:30]=[O:31]>O.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:30]=[O:31])[C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-fluorophenylcarbamate (42.7 g, 202 mmol) was concentrated from toluene in vacuo (3×) to remove any traces of water. The resulting residue was dissolved in tetrahydrofuran (600 mL), and cooled to −78° C. To this was added tert-butyllithium (1.7 M in pentane, 285 mL, 485 mmol) in dropwise fashion. After addition was complete, the reaction was stirred at −78° C. for 30 minutes. The solution was allowed to gradually warm to −20° C. before re-cooling to −78° C. To this was added dimethylformamide (46.9 mL, 606 mmol). The reaction was allowed to gradually warm to room temperature overnight. The reaction was poured into a separatory funnel containing diethyl ether and water. The organics were washed with water (3×) and concentrated. The combined aqueous washes were neutralized with 1 M potassium bisulfate and extracted with diethyl ether. The ethereal layers were combined with the other organics, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 48.1 g (100%) as a yellow oil which was used without further purification. 1H-NMR (CDCl3, 500 MHz) δ 1.50 (s, 9H), 7.27 (m, 1H), 7.35 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.85 (bs, 1H), 9.99 (d, J=1.2 Hz, 1H). Mass spec.: 262.16 (MNa)+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.Cl[P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28].[NH4+].[Cl-]>C1COCC1>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: Cc1ccc2ccccc2n1
Reactant: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15 g, 150 mmol) in THF (250 mL) was added n-BuLi (2.5 M in hexane, 59 mL, 150 mmol) at −78° C. under a nitrogen atmosphere. The resulting solution was stirred at −45° C. for 0.5 h, then cooled to −78° C., and 2-methylquinoline (10 g, 70 mmol) was added. The resulting solution was stirred at −78° C. for 0.5 h and then diethyl chlorophosphonate (14 g, 80 mmol) was added. The reaction mixture was stirred at −78° C. for 1 h and then at rt for 1 h. The reaction mixture was treated with saturated NH4Cl (300 mL) and extracted with EtOAc (3×350 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)) to obtain compound 58a as a yellow oil. Mass Spectrum (LCMS, ESI pos.) Calcd. For C14H18NO3P: 280.1 (M+H). Found 280.2.
Reaction SMILES: [CH3:1][C:2]1[C:22]([C:23]([O:25]CC)=[O:24])=[C:5]2[CH:6]=[C:7]([CH3:21])[CH:8]=[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])[N:4]2[N:3]=1.[OH-].[Na+].Cl>O1CCOCC1>[CH3:1][C:2]1[C:22]([C:23]([OH:25])=[O:24])=[C:5]2[CH:6]=[C:7]([CH3:21])[CH:8]=[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])[N:4]2[N:3]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3c(F)ccc(F)c3F)cc(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(F)ccc(F)c2F)n2nc(C)c(C(=O)O)c2c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 56.5 %

Procedure:
700 mg (1.81 mmol) of ethyl 2,5-dimethyl-7-[(2,3,6-trifluorobenzyl)oxy]pyrazolo[1,5-a]pyridine-3-carboxylate from Example 9A were initially charged in 18 ml of dioxane and heated to 90° C. 4.5 ml of dioxane and 7.25 ml (14.50 mmol) of 2 N aqueous sodium hydroxide solution were added, and the reaction mixture was stirred at 90° C. for two days. Another 3.63 ml (7.26 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at 90° C. for a further 2 hours. The reaction solution was admixed with 15 ml of 1 N aqueous hydrochloric acid and stirred for 30 min. In the course of this, solids precipitated out. This suspension was filtered, and the solids filtered off were washed with a little water and dried under high vacuum. 358 mg of the target compound were obtained (54% of theory).