Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][CH2:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+].C(OC(=O)C)(=O)C.C(Cl)Cl>O>[C:22]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:10]=2[O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:15]1)(=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1OCc1ccccc1)CCNC2
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1OCc1ccccc1)CCN(C(C)=O)C2
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A mixture of 122.3 g of 5-benzyloxy-1,2,3,4-tetrahydro-6-methoxy-isoquinoline-hydrochloride, 36.1 g of sodium acetate, 81.7 g of acetic anhydride, and 500 ml of methylene chloride is stirred for 1 hour at the boiling point. After cooling, the mixture is combined with 500 ml of water and the organic phase is separated and evaporated to dryness under reduced pressure. 99.5 g of 2-acetyl-5-benzyloxy-1,2,3,4-tetrahydro-6-methoxy-isoquinoline are obtained. m.p. = 94° - 95° C. (ethyl acetate - diisopropyl ether).
Reaction SMILES: CCO[C:4]([CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5].C[S:15][C:16](=S)[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH2:12]([O:11][C:9]([CH2:8][N:7]1[CH2:6][C:4](=[O:5])[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:16]1=[S:15])=[O:10])[CH3:13]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CSC(=S)Nc1ccccn1
Product: CCOC(=O)CN1CC(=O)N(c2ccccn2)C1=S
Temperature: 100 °C
Yield: 66.3 %

Procedure:
18.9 g of diethyliminodiacetate and 18.4 g of methyl-2-pyridyldithiocarbamate were put in a flask and heated to 100° C. for 5 hours. The product was subjected to silica gel column chromatography and fractions were extracted by a solvent mixture composed of n-hexane-ethyl acetate (1:1), were gathered to obtain 18.5 g of 1-ethoxycarbonylmethyl-3-(2-pyridyl)-2-thiohydantoin as a viscous oil. 5.6 g of this 2-thiohydantoin compound, 6.8 g of 4-[2-(2-anilonovinyl)-3-benzoxazolio]butanesulfonate and 100 ml of ethanol were put in a flask. After adding 4 ml of acetic anhydride and 6 ml of triethylamine, the mixture was heated under refluxing for 30 minutes. After condensing to remove the solvent, 200 ml of ethyl acetate was added thereto. After stirring for 30 minutes, the supernatant liquid was removed by decantation. 10 ml of methanol was added to dissolve the residue, and a solution prepared by dissolving 2.4 g of potassium acetate in 10 ml of methanol was added. After heating for 10 minutes, it was allowed to stand. Separated crystals were filtered and recrystallized with methanol to obtain 6.2 g of Compound (19) as orange crystals having a melting point of 202° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2C#N)=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(Cl)(=O)C([Cl:28])=O>CN(C=O)C.ClCCl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:16]=2)=[CH:9][C:5]([C:6]([Cl:28])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2ccc(C(F)(F)F)nc2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring dichloromethane solution (5 mL) containing 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid (Step 38C or 38C.1, 436 mg, 1.2 mmol), was added 2 drops of DMF and then oxalyl chloride (128 μL, 1.5 mmol) under N2. The mixture was stirred at rt for 2 hrs and concentrated to yield 4-chloro-2-methoxy-5-(6-trifluoromethyl-pyridin-3-yl)-benzoyl chloride as a solid, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19](O)=[O:20])=[N:8][C:9]=2[O:10][C@H:11]([C:15]([F:18])([F:17])[F:16])[CH2:12][CH2:13][OH:14])[CH2:3][CH2:2]1.[NH2:22][C:23]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:24]([NH:26][CH3:27])=[O:25]>>[CH2:28]([C:23]([NH:22][C:19]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:9]([O:10][C@H:11]([C:15]([F:16])([F:18])[F:17])[CH2:12][CH2:13][OH:14])[N:8]=1)=[O:20])([C:24](=[O:25])[NH:26][CH3:27])[CH2:30][CH3:31])[CH3:29]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(C2CC2)c(O[C@@H](CCO)C(F)(F)F)n1
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(O[C@@H](CCO)C(F)(F)F)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (Example 319a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C1(=O)O[CH2:15][CH2:14][O:13]1>CN(C=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:15][CH2:14][OH:13]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=C1OCCO1
Solvent: CN(C)C=O
Product: OCCOc1cccc(C(F)(F)F)c1
Yield: 64 %

Procedure:
The title compound was prepared according to the procedure of Example 114, Step 1 starting from 3-trifluoromethylphenol (3.89 g, 24 mmol) and ethylene carbonate (1.76 g, 20 mmol) with the exception that no DMF was used. Oil; yield 64%. MS m/z 206 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:29])[CH:3]=1.[CH3:30][C@@H:31]1[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[NH:32]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:32]5[C@H:31]([CH3:30])[CH2:35][CH2:34][S:33]5(=[O:37])=[O:36])=[CH:3][C:4]=4[F:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:24][CH2:23]1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Product: C[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C(F)(F)F)cc3C3CC3)CC2)c(F)c1
Yield: 29.3 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 123 and (R)-3-methylisothiazolidine 1,1-dioxide (107 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 4, the title compound (122 mg) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:18]([CH2:17][C:13]1[CH:12]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[CH:16]=[CH:15][CH:14]=1)[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:21]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)S(=O)(=O)NCc1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)S(=O)(=O)N(Cc1cccc(-c2cccc(S(C)(=O)=O)c2)c1)Cc1ccccc1F

Procedure:
In analogy to example 10, step 3, propane-2-sulfonic acid (3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide (example 49, step 2) was reacted with 2-fluorobenzyl bromide, tetrabutylammonium iodide and cesium carbonate in N,N-dimethylacetamide to give propane-2-sulfonic acid (2-fluoro-benzyl)-(3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide as a colorless solid. MS: 476.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14]OCC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:35]([C:37]1[CH:38]=[N:39][C:40]([OH:43])=[CH:41][CH:42]=1)#[N:36].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:14][O:43][C:40]3[CH:41]=[CH:42][C:37]([C:35]#[N:36])=[CH:38][N:39]=3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)nc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: N#Cc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c), 3-cyano-6-hydroxy-pyridine and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate and a reaction time of 18 h. Light yellow solid (41%). MS (Turbo Spray): m/z=493.2 [M+H].
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)[OH:4].[H][H]>CO.[Pd]>[F:22][C:2]([F:1])([F:21])[CH:3]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[OH:4]
Reactant: O=C(OCc1ccccc1)N1CCC(C(O)C(F)(F)F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OC(C1CCNCC1)C(F)(F)F

Procedure:
A suspension of 3.11 g (9.80 mmol) of benzyl 4-(2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate and 300 mg Pd/C (10%) in 30 mL of MeOH was hydrogenated at RT and 3 bar hydrogen pressure for 4 hours. The catalyst was filtered off and the filtrate was evaporated down in vacuo. Yield: 1.82 g (quant. yield); C7H12F3NO (M=183.172); calc.: molpeak (M+H)+: 184; found: molpeak (M+H)+: 184; Rf value: 0.20 (silica gel, EtOAc/MeOH/conc. aqueous ammonia 5:5:0.5).
Reaction SMILES: [C:1]([CH:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6](Cl)=[O:7])#[N:2].[CH2:21]([OH:26])[C:22]#[C:23][CH2:24][OH:25].N1C=CC=CC=1.O>C1C=CC=CC=1.C1COCC1>[C:1]([CH:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6]([O:25][CH2:24][C:23]#[C:22][CH2:21][OH:26])=[O:7])#[N:2]
Reactant: OCC#CCO
Reactant: N#CC(c1ccccc1)C(CC(=O)Cl)c1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#CC(c1ccccc1)C(CC(=O)OCC#CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 10.7 g (0.038 mol) of 4-cyano-3,4-diphenylbutyryl chloride in 30 ml of benzene was added over a 45 minute period to a stirred solution of 6.5 g (0.076 mol) of 2-butyn-1,4-diol and 3.4 ml of pyridine in 100 ml of THF at 0°. The reaction mixture was stirred for 24 hours at room temperature in a flask equipped with a Drierite tube. The solution was poured into 50 ml of water and the layers were separated. Two 60-ml ether extractions of the aqueous layer were combined with the THF layer, were washed twice with 100 ml of H2O, with 100 ml saturated aqueous sodium bicarbonate, and with 100 ml saturated aqueous sodium chloride and were stirred over MgSO4. The filtered solution was stripped and purified by column chromatography on silica gel (hexanes/methylene chloride) to give two fractions weighing 12.6 g (47%) having different isomer ratios as determined from the nmr spectra. The infrared and nmr spectra are in accord with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][CH:3]=1.CC(O)=O.CO>[Zn].CCO>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: Nc1ccc(Br)nc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.3 %

Procedure:
To a stirred mixture of 6-bromo-3-nitro-2-pyridinamine (2.5 g, 11.47 mmol) in a mixture of glacial HOAc (10 mL), MeOH (10 mL) and EtOH (10 mL) at 0° C. was added portionwise zinc dust (3.73 g, 57.35 mmol). The mixture was stirred at rt for 15 h. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned between saturated aq NaHCO3 and EtOAc. The organic layer was separated and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, separated and dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-bromopyridine-2,3-diamine (1.30 g, 60%) as a solid that did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 6.61 (d, J=7.7 Hz, 1H), 6.47 (d, J=7.7 Hz, 1H), 5.82 (s, 2H), 4.79 (s, 2H). LCMS (ESI) m/z 188 and 190 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][NH:10][C:9](=O)[N:8]=1.O.[OH-].[Na+].O.[NH2:18][NH2:19]>P(Cl)(Cl)(Cl)=O.C(Cl)Cl.CO>[NH:18]([C:9]1[N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[CH:11][N:10]=1)[NH2:19]
Reactant: NN
Reactant: O=c1nc(-c2ccccn2)cc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: NNc1nccc(-c2ccccn2)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To a solution of 2-amino-4-(2-pyridyl)pyrimidine (10.10 g, 58.66 mmol) in 5% aqueous sulfuric acid (200 mL) was added sodium nitrate (20.24 g, 293.3 mmol) portionwise over 10 min. The solution was stirred at room temperature for 2 h and was then adjusted to pH 10 by addition of 6N aq. NaOH. The resulting mixture was then extracted with 30% i-PrOH in CHCl3 (10×300 mL), and the combined organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was triturated with hexanes and collected by vacuum filtration to afford 6.89 g of 4-(2-pyridyl)pyrimid-2-one (68%) as a beige solid. A mixture of 4-(2-pyridyl)pyrimid-2-one (6.89 g, 39.8 mmol) in phosphorus oxychloride (30 mL) was heated at 110° C. for 90 min in a sealed tube. The dark brown solution was then cooled to room temperature and poured over cracked ice and water (500 mL). The mixture was vigorously stirred at 0° C. for 1 h, and was then adjusted to pH 14 with 6 N aq NaOH. The mixture was extracted with CH2Cl2 (2×300 mL), and the combined organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. To a solution of the residue in CH2Cl2 (10 mL) and MeOH (30 mL) was added hydrazine monohydrate (7.0 mL, 144.2 mmol), and the solution was stirred for 16 h at which time a white precipitate was observed. This solid was collected by vacuum filtration, washed with water, and dried in vacuo to provide 2.20 g of the title compound (30%) as an off-white solid. MH+188.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][C:22]([C:31]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][NH:34]3)=[O:32])=[N:21]2)=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][C:22]([C:31]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][N:34]3[C:8](=[O:10])[CH3:9])=[O:32])=[N:21]2)=[CH:16][CH:15]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-n2nc(C(=O)N3CCCCN3)cc2-c2ccccn2)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)N3CCCCN3C(C)=O)cc2-c2ccccn2)cn1
Reaction time: 0.33 h

Procedure:
Triethylamine (0.210 mL), acetyl chloride (0.0807 mL) and 4-dimethylaminopyridine (13.5 mg) were added to 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]hexahydropyridazine (0.275 g) obtained in Example 162 in methylene chloride (6.0 mL) at room temperature, followed by stirring for 20 minutes. The mixture was partitioned between water and chloroform. The organic layer was washed with saturated brine, and then dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an amorphous product (0.149 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[CH:4][C:5](Br)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([CH:12]2[CH2:14][CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(N)c(F)cc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc(N)c(F)cc1C1CC1
Temperature: 110 °C
Yield: 61 %

Procedure:
The product from the above reaction (5-amino-2-bromo-4-fluorobenzonitrile) (4.0 g, 18.6 mmol), cyclo-propyl boronic acid (3.19 g, 37.2 mmol), Pd(OAc)2 (835 mg, 3.72 mmol), tricyclohexyl phosphine (1.04 g, 3.72 mmol), Cs2CO3 (36.3 g, 111.6 mmol) were combined in a pressure vessel. A mixture of toluene (110 ml) and H2O (35 ml) was added. The ensuing yellow-orange suspension was degassed and flushed with nitrogen gas (3×). The pressure vessel was sealed and heated over night (ca. 12 h) at 110° C. After checking the reaction by TLC and HPLC, the precipitate/salts were filtered off, more H2O was added and the mixture was extracted with ethyl acetate (3×). The combined organic phases were filtered through Na2SO4, silica gel was added and solvents were removed using a rotary evaporator. Further purification by CombiFlash (120 g column) eluting with hexanes/ethyl acetate (0→20% gradient) yielded 2.01 g (61%) of the desired product in form of a pale yellow, beige solid. 1H NMR (300 MHz, cdcl3) δ 6.98 (d, J=8.6 Hz, 1H), 6.58 (d, J=12.0 Hz, 1H), 3.81 (s br, 2H), 2.21-2.06 (m, 1H), 1.11-0.99 (m, 2H), 0.69-0.59 (m, 2H); MS (ES) 177 (M+H).
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]3=[N:8][N:7]=2)=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[Cl:22][C:23]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C([O-])(O)=O.[Na+]>ClCCl.CO.C(OCC)(=O)C>[Cl:22][C:23]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:13]1[CH2:12][CH2:11][N:10]2[C:6]([C:5]3[S:1][N:2]=[CH:3][N:4]=3)=[N:7][N:8]=[C:9]2[CH2:14]1)=[O:26]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: c1nsc(-c2nnc3n2CCNC3)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(c1cccc(Cl)c1Cl)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I115) (50 mg, 0.240 mmol) and triethylamine (0.050 mL, 0.360 mmol) in Dichloromethane (DCM) (1.5 mL) was treated with 2,3-dichlorobenzoyl chloride (55.3 mg, 0.264 mmol, commercially available) and stirred at room temp for 1 hr. After 1 hr, 2 drops of methanol and then NaHCO3 solution (5 ml) and ethyl acetate (30 ml) were added and the product was extracted into the ethyl acetate which was dried (Na2SO4) and concentrated. Purification by high pH MDAP gave desired material as a white solid in 76 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][N:19]=4)[CH:14]=[C:13]([C:21]([O:23]CC)=[O:22])[C:12]3=[O:26])[CH:9]=[CH:10][C:2]1=2.O.[OH-].[Li+].O>O1CCOCC1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][N:19]=4)[CH:14]=[C:13]([C:21]([OH:23])=[O:22])[C:12]3=[O:26])[CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)c1cc2cccnc2n(-c2ccc3c(c2)OCCO3)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2cccnc2n(-c2ccc3c(c2)OCCO3)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
4.3 g (12 mmol) of ethyl 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in 1,4-dioxane (100 mL), and 1.0 g (24 mmol) of lithium hydroxide monohydrate and 50 mL of water were added thereto at room temperature. The resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and a solid precipitated therefrom was dissolved in chloroform. This solution was washed with an aqueous solution of citric acid and water in this order, and was dried and concentrated. The solid thus obtained was washed with diisopropyl ether, and thus 3.96 g of the title compound was obtained as pale yellow crystals (yield: quantitative).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)#[N:2].[CH3:24][NH2:25]>C(O)C.CN(C)C=O>[C:1]([N:3]=[C:4]([NH:25][CH3:24])[NH:5][CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)#[N:2]
Reactant: CN
Reactant: CSC(=NC#N)NCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
The compound obtained in Example 212 (0.66 g, 2.01 mmol) was dissolved in a mixture of ethanol (30 ml) and dimethylformamide (50 ml). To the obtained solution, 30% methylamine in ethanol (25 ml) was added and stirred at 80° C. for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with ethanol. 0.626 g (assayed quantitatively) of the title compound was obtained as a pale yellow solid. The solid was recrystallized from chloroform--methanol--ether, to obtain the title compound as colorless needles (mp. 262°-265° C. (dec.)).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[Na+].[Na+].[CH3:19][NH:20]C>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[C:19]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12])#[N:20]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: CNC
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#N)c(O)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 33.5 %

Procedure:
To a solution of methyl 4-bromo-3-hydroxybenzoate (1.01 g, 4.4 mmol) in 7 ml of dimethylamine was added Pd(OAc)2 (15 mg, 0.5 mol %), sodium carbonate (0.47 g, 4.4 mmol) and potassium ferricyanide (0.41 g, 0.97 mmol). The mixture was heated to 120° C. and stirred at this temperature for 4 hours and at RT for 18 hours. The reaction mixture was diluted with 30 ml of ethyl acetate and the resulting slurry was filtered through Celite. The filtrate was washed with water (2×15 ml) and 5% aqueous ammonium hydroxide (1×15 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to provide methyl 4-cyano-3-hydroxybenzoate (0.26 g, 33.5% yield) (S. Weissman, D. Zewge, C. Chen; J. Org. Chem. 2005, 70, 1508-1510). 1H NMR (400 MHz, CD3OD): 7.65 (d, 1H), 7.56-7.54 (m, 2H), 3.91 (s, 3H). MS (EI) for C9H7NO3: 178 (MH+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=3[CH3:25])=[CH:8][CH:9]=2)[O:4]1.[OH-].[Na+:29]>C(O)C>[F:27][C:2]([F:1])([F:26])[C@H:3]1[C:12]([C:13]([O-:15])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=3[CH3:25])=[CH:8][CH:9]=2)[O:4]1.[Na+:29]
Reactant: Cc1cc(C)c(C)c(Oc2ccc3c(c2)O[C@@H](C(F)(F)F)C(C(=O)O)=C3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)c(C)c(Oc2ccc3c(c2)O[C@@H](C(F)(F)F)C(C(=O)[O-])=C3)c1

Procedure:
A solution of 38.1 mg (0.101 mmole) of (2R)-(−)-2-(trifluoromethyl)-7-(2,3,5-trimethylphenoxy)-2H-chromene-3-carboxylic acid in 1.5 mL of ethanol was treated with 1.00 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide 48.4 mg (quant.) of an off-white solid: MS (ES+) 379 (M+1, 100); 1H NMR (CD3OD/400 MHz) 2.01 (s, 3H), 2.24 (s, 3H), 2.26 (s, 3H), 5.76 (q, 1H, J=7.4 Hz), 6.28 (d, 1H, J=2.4 Hz), 6.38 (dd, 1H, J=8.3 Hz, J=2.4 Hz), 6.63 (s, 1H), 6.87 (s, 1H), 7.11 (d, 1H, J=8.3 Hz), 7.38 (s, 1H); 19F NMR (CD3OD/400 MHz) 80.2 (d, 3F, J=7.7 Hz).