Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40](N2C=CN=C2)=[O:41])[CH2:35][CH2:34]1)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])[CH2:35][CH2:34]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)N1CCC(NC(=O)n2ccnc2)CC1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)NC2CCN(S(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.7 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (30.5 mg, 0.072 mmol) and imidazole-1-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide (75.4 mg, 0.277 mmol) in CH2Cl2 (4 mL) was stirred at rt for 72 hrs. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide (15.7 mg, 34.7%). HRMS (ES+) m/z Calcd for C29H34Cl2F2N4O3S+H [(M+H)+]: 627.1770; Found: 627.1770.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.O>[F:15][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc2ccnc(Cl)c2cc1F
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2ccnc(F)c2cc1F
Temperature: 145 °C
Yield: 68.7 %

Procedure:
To a solution of 1-chloro-7-fluoro-6-methoxyisoquinoline (1.5 g, 7.09 mmol) in DMSO was added cesium fluoride (2.15 g, 14.18 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (950 mg, 68%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.0-7.98 (m, 1H), 7.77-7.74 (d, J=12 Hz, 1H), 7.42-7.40 (m, 1H), 7.21-7.19 (m, 1H), 4.04 (s, 3H); 19F NMR: δ ppm −129.05 (1F), −71.98 (1F); MS: MS m/z 196.1 (M++1).
Reaction SMILES: Cl.C([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])C.[CH2:10]([C:12]1[CH:21]=[C:20]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[C:31]([CH3:33])[C:30]([CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:29][N:28]=3)[O:24][N:23]=2)[CH:19]=[C:18]([CH3:38])[C:13]=1[O:14][CH2:15][CH2:16]N)[CH3:11].C(N(CC)CC)C>C(O)C>[CH2:10]([C:12]1[CH:21]=[C:20]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[C:31]([CH3:33])[C:30]([CH2:34][CH:35]([CH3:36])[CH3:37])=[CH:29][N:28]=3)[O:24][N:23]=2)[CH:19]=[C:18]([CH3:38])[C:13]=1[O:14][CH2:15][CH2:16][NH:8][CH2:7][CH2:6][C:5]([OH:4])=[O:9])[CH3:11]
Reactant: CCOC(=O)CCN
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCNCCC(=O)O
Temperature: 80 °C
Reaction time: 18 h
Yield: 27.1 %

Procedure:
A solution of β-alanine ethyl ester hydrochloride (88 mg, 570 μmol) in ethanol (2 mL) is filtered over PL-HCO3 MP SPE ion exchange. The methanesulfonic acid ester intermediate of Example 48 (90 mg, 190 μmol) and triethylamine (77 mg, 760 μmol) is added to the filtrate and the mixture is stirred in a sealed vial at 80° C. for 18 h. The mixture is cooled to rt and the solvent is evaporated. The crude 3-(2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-ethylamino)-propionic acid ethyl ester is dissolved in ethanol (2 mL) and 1 N aq. NaOH (2 mL) and the mixture is stirred at rt for 3 h. The mixture is neutralised by adding 1 N aq. HCl, the solvent is removed in vacuo and the residue is separated by prep. HPLC to give the title compound (24 mg) as a white solid; LC-MS: tR=0.90 min, [M+H]+=466.79; 1H NMR (CDCl3): δ1.00 (d, J=6.5 Hz, 6H), 1.30 (t, J=7.3 Hz, 3H), 1.90-1.99 (m, 1H), 2.38 (s, 3H), 2.46 (s, 3H), 2.60-2.68 (m, 4H), 2.73 (q, J=7.5 Hz, 2H), 3.20-3.27 (m, 2H), 3.27-3.33 (m, 2H), 4.07-4.15 (m, 2H), 7.92 (s, 1H), 7.94 (s, 1H), 8.08 (s, 1H), 8.54 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:39][C:40](=[O:53])[C@@H:41]([O:50][CH2:51][CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[CH3:38].N(C(OCC)=O)=NC(OCC)=O>>[CH2:37]([O:39][C:40](=[O:53])[C@@H:41]([O:50][CH2:51][CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:45][CH:44]=1)[CH3:38]
Reactant: OC/C=C(/c1ccccc1)c1ccc(F)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(/c2ccccc2)c2ccc(F)cc2)cc1)OCC
Yield: 73 %

Procedure:
Reaction of (Z)-3-(4-fluorophenyl)-3-phenyl-prop-2-en-1-ol (200 mg, 0.88 mmol), triphenylphosphine (242 mg, 0.92 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (200 mg, 0.84 mmol) and diethyl azodicarboxylate (160 mg, 0.92 mmol) in an identical manner to example 1 gave the title compound (275 mg, 73%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].C(N(C(C)C)CC)(C)C.Br[CH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CCBr)cc1
Reactant: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCNCc2ccccn2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Commercially available 2-picolylamine (0.625 ml) was dissolved in toluene (15 ml) and diisopropylethylamine (0.715 ml) was added. After the addition of the compound obtained in Example 9-1 (499.7 mg), the mixture was stirred for two days at 80° C. After the reaction, toluene was added. The solution was washed with distilled water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by istillation under reduced pressure, and the residue was purified by silica gel column chromatography (25 g, chloroform/methanol=25/1) to obtain the title compound (400.1 mg) as light brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH3:13]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccccc1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Product: CC(=NNc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
10.2 g of acetophenone -p-nitrophenylhydrazone (melting point: 186.5-188.0° C.) obtained by equimolar reaction of p-nitrophenylhydrazine and acetophenone was subjected to Vilsmeir reaction with phosphorus oxychloride and dimethylformamide to obtain 11.8 g of 1-(p-nitrophenyl)-3-phenylpyrazole-4-carboxyaldehyde (melting point: 208.5-211.0° C.) having the following structural formula. ##STR300##
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:13]1[CH2:14][CH2:15][CH:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=4)[CH:17]=[CH:16][C:5]=3[N:6]=2)[CH2:11][CH2:12]1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a degassed solution of 6-bromo-2-(piperidin-4-yloxy)benzo[d]thiazole (800 mg, 2.55 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.185 g, 3.83 mmol) and potassium carbonate (1.412 g, 10.22 mmol) in dioxane (21 mL) and water (7 mL) was added Pd(Ph3P)4 (148 mg, 0.128 mmol). The reaction mixture was stirred at 100° C. overnight. The mixture was cooled to rt, diluted with water (60 mL), and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2-MeOH gradient 0 to 20% MeOH) to afford tert-butyl 4-(2-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (923 mg, 2.221 mmol, 87% yield) as a white foam. LCMS (m/z)=416 (M+H)+.
Reaction SMILES: CN(C=O)C.[CH3:6][C@H:7]1[O:12][C@@H:11]([CH3:13])[CH2:10][NH:9][CH2:8]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[CH:26]=[CH:25][C:24]2=[N:27][C:28]([C:30]3[CH:31]=[CH:32][C:33]([C:43]([F:46])([F:45])[F:44])=[C:34]([NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=3)=[CH:29][N:23]2[N:22]=1>O>[CH3:13][C@H:11]1[O:12][C@@H:7]([CH3:6])[CH2:8][N:9]([C:21]2[CH:26]=[CH:25][C:24]3=[N:27][C:28]([C:30]4[CH:31]=[CH:32][C:33]([C:43]([F:44])([F:45])[F:46])=[C:34]([NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=4)=[CH:29][N:23]3[N:22]=2)[CH2:10]1
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(c2ccc3nc(-c4ccc(C(F)(F)F)c(NC(=O)C(C)(C)C)c4)cn3n2)C[C@H](C)O1
Temperature: 120 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
An 8 mL vial is charged with DMF (1 mL), cis-2,6-dimethylmorpholine (0.034 g), Cs2CO3 (0.130 g), and N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.0396 g, 0.1 mmol). The mixture is stirred at 120° C. for 16 hr, then diluted with H2O (5 mL) and extracted with Et2O (3 mL×2). Organics are dried and concentrated onto celite, purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.027 g, 57% yield). LCMS m/z=476.6 [M+H]+, tR=2.77 min. (compound same as Example 250)
Reaction SMILES: [CH2:1]([C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([N:12]([CH3:14])[CH3:13])[S:9]2)[C@@H:5]([O:15]CC2C=CC(OC)=CC=2)[C@@H:4]1[O:25]CC1C=CC(OC)=CC=1)[CH3:2].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[CH3:14][N:12]([CH3:13])[C:8]1[S:9][C@H:10]2[O:11][C@H:3]([CH2:1][CH3:2])[C@@H:4]([OH:25])[C@H:5]([OH:15])[C@H:6]2[N:7]=1
Reactant: CC[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 28.9 %

Procedure:
A solution of above crude product 41 (260 mg, purity 54% by LC-MS) in dichloromethane (10 mL) was treated with TFA (1 mL) for 4 hours at room temperature. The solution was adjusted to pH at 8 with NH4OH, and then condensed to give a crude product, which was purified by Prep-HPLC with the following conditions (Agilent 1200 prep HPLC: Column, SunFire Prep C18,19*50 mm 5 um; mobile phase, WATER with 0.03% NH4OH and CH3CN (10% CH3CN up to 45% in 10 min; Detector, UV 220 nm) to provide compound 42 (Example 6) as a white solid (38 mg). (ES, m/z): [M+H]+ 247.0. 1H NMR (300 MHz, D2O) δ 6.18-6.21 (d, J=6.6 Hz, 1H), 4.09-4.13 (t, J=6.0 Hz, 1H), 3.91-3.94 (t, J=4.8 Hz, 1H), 3.42-3.44 (m, 2H), 2.92 (s, 6H), 1.69-1.77 (m, 1H), 1.40-1.50 (m, 1H), 0.84-0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:15]([NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[O:18])[C:14](=[O:29])[N:13]([CH2:30][C:31]([O:33]CC)=O)[C:12]3[CH:36]=[CH:37][CH:38]=[CH:39][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[NH3:40]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:15]([NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[O:18])[C:14](=[O:29])[N:13]([CH2:30][C:31]([NH2:40])=[O:33])[C:12]3[CH:36]=[CH:37][CH:38]=[CH:39][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: N
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)c2ccc3ccccc3c2)C(c2ccc(OC)cc2)Sc2ccccc21
Solvent: CO
Product: COc1ccc(C2Sc3ccccc3N(CC(N)=O)C(=O)C2NC(=O)c2ccc3ccccc3c2)cc1
Reaction time: 72 h

Procedure:
In 500 ml of methanol is dissolved 1.8 g of ethyl 2-p-methoxyphenyl- 3-(2-naphthalenecarboxamido)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, into which ammonia gas is blown under ice-cooling for about 1 hour. After the mixture is allowed to stand still at room temperature for 3 days, the reaction mixture is concentrated under reduced pressure to the volume of about 50 ml to give crystals. The crystals are collected by filtration to give 1.2 g of 2-p-methoxyphenyl-3-(2-naphthalenecarboxamido)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, m.p. 243°-245° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][CH:23]=1>>[OH:20][C:14]1[CH:13]=[CH:12][C:11]([N:10]=[N:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][C:15]=1[C:16]([NH:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][CH:23]=1)=[O:17]
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc4cn[nH]c4c3)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride and 6-aminoindazole were reacted together as described in Preparation 7. The product was crystallized in aqueous pyridine, m.p. 279°, λmax (methanol)=350 nm.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:20])=[C:14]2[CH:15]=[N:16][N:17]([CH2:18][CH3:19])[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1O

Procedure:
253 g. of [[(1-Ethyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester (0.09 mol.) are dissolved in 770 g. of diphenyl ether. The reaction mixture is heated to 235°-250° (bath temperature) and allowed to react at this temperature for 1-2 hours while the resulting ethanol is continuously distilled off. The last amount of alcohol is removed by means of a water aspirator. The diphenyl ether is separated by distillation with a fractionating column in vacuo. The 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is obtained at b.p.0.05 115°-120°, yield 195 g.= 92% of theory, m.p. 85°-87°. The compound is recrystallized from benzene (90° to 100°), m.p. 87°-89°.
Reaction SMILES: CS(C1C=C[C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].N1CCCCC1>>[CH3:31][NH:30][S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:14]2[CH2:8][CH2:15][CH2:16][CH2:17][CH2:18]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc(N2CCCCC2)c(C(=O)O)c1
Yield: 48 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-methylsulfamoyl-benzoic acid and piperidine and obtained in 48% yield. MS (m/e): 297.4 MH−(100%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][C:31]1[O:35][C:34]([C:36](O)=[O:37])=[N:33][N:32]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:36]([C:34]4[O:35][C:31]([CH3:30])=[N:32][N:33]=4)=[O:37])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: Cc1nnc(C(=O)O)o1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)c2nnc(C)o2)C3)cc1

Procedure:
Compound fa was prepared according to the procedure described in Example 213 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 5-methyl-1,3,4-oxadiazole-2-carboxylic acid. LC-MS: m/z=+507 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH:15]=3)[N:10]([CH3:23])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:26]>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:21])([CH3:22])[C:19]([OH:26])=[O:20])[CH:15]=3)[N:10]([CH3:23])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)CO)ccc2n1C
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Reaction time: 8 h

Procedure:
A solution of 6.0 g (60 m mole) of chromium trioxide in 50 ml of glacial acetic acid and 5 ml of water was added dropwise to a mixture of 19.0 g (55 m mole) of 2-[3-(4-chloro-phenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methylpropanol, 50 ml of glacial acetic acid, 10 ml of water, and 5 ml of conc. sulfuric acid under stirring. After standing overnight, the reaction mixture was warmed for one hour on a steam bath. Subsequently the mixture was extracted with chloroform. The chloroform extracts were dried, and the evaporation residue was chromatographed on silicagel with chloroform/methanol (8:2) as eluant.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:4][CH:3]=1.CN(C)[C:31](=[O:33])[CH3:32]>C(OCC)(=O)C.CCCCCC>[C:31]([C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:6][CH:7]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)N(C)C
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1ccc(C2c3cc(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)cc1
Yield: 20 %

Procedure:
Using N-(3-(4-bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 284 and N,N-dimethylacetamide, the title compound was synthesized in the same manner as in Example 292. Yield: 20%. Melting point: 195-196° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:20])CC)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][F:20])[CH:3]=1
Reactant: OCCCCCc1cccc(Br)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: FCCCCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 5-(3-bromophenyl)pentan-1-ol (0.63 g, 2.6 mmol) in methylene chloride at −78° C. was treated with a solution of diethylamino sulfur trifluoride (DAST) (0.7 mL, 5.2 mmol) in methylene chloride, allowed to warm to room temperature, stirred for 0.5 h at room temperature, poured into water and extracted with ether. The extracts were combined washed sequentially with saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by flash chromatography on silica gel, 40:1 hexane/ethyl acetate as eluent to give 1-bromo-3-(5-fluoropentyl)benzene as a pale yellow oil, 0.4 g (63% yield); 1H NMR (DMSO-d6) δ 1.3 (m, 2H); 1.6 (m, 4H); 2.5 (t, 2 H); 4.4 (dxt, 2H); 7.2 (m, 2 H); 7.4 (m, 2 H); MS [(+)ESI] m/z=245 [M−H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:13]=[CH:12][C:11]([OH:14])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1)[CH3:2].CI.[C:18](=O)([O-])O.[Na+]>CN(C=O)C>[CH3:18][O:9][C:8](=[O:10])[C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][C:11]=1[OH:14])[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CCOC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1ccc(O)c(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 4-hydroxyisophthalic acid 1-ethyl ester (4.51 g) in DMF (36 mL) were added methyl iodide (3.66 g) and sodium hydrogen carbonate (2.16 g). The mixture was stirred at 60° C. for 2 hours and then allowed to stand for cooling down to room temperature. The resulting precipitated solid formed upon addition of water was filtered off to give the title compound (4.20 g).
Reaction SMILES: [CH:1]1([C:5]2[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19]([NH:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[N:10]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccnc(C2CCC2)n1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccnc(C2CCC2)n1

Procedure:
This compound was obtained according to example 2, step B] from 2-cyclobutyl-pyrimidin-4-ylamine (0.15 g), and 3-chloro-2-methyl-benzenesulfonyl chloride (0.27 g) as a light brown solid (47 mg). MS (ESI): 338.1 (MH+).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][OH:36])[CH:29]=1)[CH2:10][NH:11][C@H:12]([CH3:27])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([O:25]C)=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[Si:1]([O:8][C@H:9]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][OH:36])[CH:29]=1)[CH2:10][NH:11][C@H:12]([CH3:27])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Cc1ccc2[nH]c(C(=O)O)cc2c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylate (Preparation 12, 0.30 g, 0.59 mmol) in 1,4-dioxane (10 ml) was treated with a solution of sodium hydroxide (59 mg, 1.46 mmol) in water (1 ml) and the resulting mixture left to stir at room temperature for 30 minutes. After this time the reaction mixture was heated to 90° C. for 30 minutes and then cooled to room temperature. The solvent was removed in vacuo and the residue re-dissolved in water (20 ml) and pH adjusted to 7 by addition of 2N Hydrochloric acid. The solid that formed was filtered off, solubilised in a mixture of dichloromethane and methanol (20 ml 90:10 by volume), dried (magnesium sulphate) and the solvent removed in vacuo to give the title compound as a pale orange foam.