Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([O:37][CH3:38])[N:36]=2)[N:33]=1.[Cl-].[Na+]>CN(C)C=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([O:37][CH3:38])[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: COc1cn2nc(Cl)ccc2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cn2nc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 45.3 %

Procedure:
758 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 40 ml of N,N-dimethylformamide; 102 mg of a 60% sodium hydride dispersion in mineral oil was added, followed by stirring at 60° C. for 40 minutes. After cooling, 428 mg of 6-chloro-2-methoxyimidazo[1,2-b]pyridazine was added, followed by stirring at 100° C. for 2.5 hours. After cooling, ice water and sodium chloride were added, followed by extraction with ethyl acetate-tetrahydrofuran (1:2); the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; the crystal precipitated was recrystallized from ethanol to yield 499 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17]C)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32]Br)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:19]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][C:39](=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:32][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(-c2cccc(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
1 g (4.1 mmol) of ethyl 3′-hydroxybiphenyl-4-carboxylate, 1.98 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 600 mg of potassium carbonate are dissolved in 40 mL of 2-butanone. The mixture is brought to reflux (80° C.) and then stirred for 4 hours. After cooling, the reaction medium is filtered and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, to give a white solid (m.p.=71-72° C.) (m=2.18 g; Y=88%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[N:18][CH:19]=1>CN(C=O)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[N:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[O:3])=[CH:15][CH:16]=1
Reactant: Fc1ccccc1-c1ccc(CCCBr)cn1
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccccn1CCCc1ccc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8.2 mg (0.18 mmol) of sodium hydride (55% suspension in mineral oil) were added to 17.8 mg (0.19 mmol) of 2-hydroxypyridine in 5 ml of DMF, and the mixture was stirred at room temperature for 30 min. Subsequently, 50 mg (0.17 mmol) of 5-(3-bromopropyl)-2-(2-fluorophenyl)pyridine were added. The reaction mixture was stirred for 4 h, concentrated, admixed with water and extracted with methylene chloride. The organic phase was separated and concentrated, and the residue was purified by preparative HPLC (RP18, acetonitrile/water containing 0.1% TFA) Yield: 11 mg (22%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.Cl.[NH2:6][C@@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]=2[C:17]#[N:18])[C@H:8]1[OH:27].[Cl-].[Na+]>CO>[CH2:20]([O:19][C:12]1[C:13]([C:17]#[N:18])=[C:14]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([OH:27])[C@H:7]([NH:6][CH:2]([CH3:4])[CH3:1])[CH2:16][CH2:15]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)=O
Reactant: N#Cc1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)N[C@@H]1CCc2c(ccc(OCc3ccccc3)c2C#N)[C@H]1O
Reaction time: 2 h

Procedure:
In a mixture of 15 m. acetone and 20 ml. methanol is dissolved 450 mg. of trans-2-amino-6-benzyloxy-5-cyano-1-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride and, while nitrogen gas is introduced, 150 mg. of the adduct of lithium cyanoborohydride-dioxane complex is added in small portions at 5°-10° C. After stirring for 2 hours, a saturated aqueous solution of sodium chloride is added and the mixture is extracted with ethyl acetate. The ethyl acetate layers are washed with a saturated aqueous solution of sodium chloride and dried. The solvent is distilled off under reduced pressure and the residue is recrystallized from ethanol-ethyl acetate. The procedure yields white crystals of trans-6-benzyloxy-5-cyano-1-hydroxy-2-isopropylamino-1,2,3,4-tetrahydronaphthalene. This compound is in agreement with the sample according to the prcedure of Example 3. Yield 297 mg.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CCN(CC)CC.[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][S:26](Cl)(=[O:28])=[O:27].O>O1CCOCC1>[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][S:26]([NH:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)Cc1ccccc1I
Reactant: COC(=O)c1scnc1N
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1scnc1NS(=O)(=O)Cc1ccccc1I
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2 g (12.64 mmol) of methyl 4-amino-1,3-thiazole-5-carboxylate were dissolved together with 5.1 ml (63.2 mmol) NEt3 in 20 ml of dioxane, and 4.4 g (13.9 mmol) of (2-iodophenyl)methanesulfonyl chloride were added at room temperature. The reaction mixture was stirred at RT for 5 h. Then 40 ml of water were added and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed with 2N HCl, dried and concentrated. The residue was purified by means of column chromatography (SiO2, gradient ethyl acetate/n-heptane 10:90 to 75:25). This gave 4.3 g of methyl 4-{[(2-iodobenzyl)sulfonyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]3=[O:29])=[CH:12][CH:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]=1[NH:46][C:47]([C:49]1[S:53][C:52]2[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=2[CH:50]=1)=[O:48].C(=O)([O-])[O-].[Na+].[Na+].Cl>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.O.CN(C=O)C>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]([NH:9][C:10]3[N:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]4=[O:29])=[CH:12][CH:11]=3)[C:5](=[O:8])[NH:6][N:7]=2)=[CH:33][C:32]=1[NH:46][C:47]([C:49]1[S:53][C:52]2[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=2[CH:50]=1)=[O:48]
Reactant: CC1(C)OB(c2ccc(F)c(NC(=O)c3cc4c(s3)CCCC4)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3cc(Cl)n[nH]c3=O)nc2)C(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3cc(-c4ccc(F)c(NC(=O)c5cc6c(s5)CCCC6)c4)n[nH]c3=O)nc2)C(=O)C1
Temperature: 100 °C
Reaction time: 96 h
Yield: 26.6 %

Procedure:
In a 50-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser, 2f (240 mg, 0.570 mmol), N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (251 mg, 0.630 mmol) and sodium carbonate (181 mg, 1.71 mmol) were mixed with DMF (16.0 mL) and water (3.0 mL). This mixture was degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium (66 mg, 0.057 mmol) was added and the mixture was stirred at 100° C. (bath temperature) for 4 d. The reaction mixture was then cooled to room temperature, and water (50 mL) was added. The pH was adjusted to 6.5 with 2N hydrochloric acid and the resulting precipitate was filtered, and the filter cake was washed with ater (25 mL) and purified by column chromatography to afford a 27% yield of 2h (100 mg) as a tan foam: 1H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 10.09 (s, 1H), 9.54 (s, 1H), 8.84 (s, 1H), 8.38 (4, 1H, J=2.7 Hz), 8.03 (dd, 1H, J=7.5, 2.1 Hz), 7.75 (d, 1H, J=2.7 Hz), 7.72 (s, 1H), 7.66 (m, 1H), 7.54 (d, 1H, J=9.0 Hz), 7.41 (t, 1H, 3=10.2 Hz), 4.09 (s, 2H), 3.70 (m, 4H), 2.77 (t, 2H, J=5.5 Hz), 2.62 (t, 2H, J=5.0 Hz), 1.79 (m, 4H), 1.45 (s, 9H); MS (ESI+) m/z 659.9 (M+H).
Reaction SMILES: [N:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[NH2:1][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Nc1c(-c2ccccc2)[nH]c2ccccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
To a solution of 3-nitroso-2-phenyl indole (28) (25 gm, 0.129 mol) in ethanol (450 ml) was added 2N sodium hydroxide (300 mL, 5.0 eq) followed by sodium dithionite (38 g). The reaction was heated at reflux for 5 h, then filtered. The solid was washed with water and dried under vacuum to provide Compound 29 as a yellow solid. Yield=15 g (72.1%). ES-MS: 209.25 (M++1); NMR (DMSO-d6): δ 7.0 (m, 1H), 7.1 (m, 1H), 7.22 (m, 1H), 7.32 (m, 2H), 7.40 (m, 1H), 7.48 (m, 2H), 7.60 (m, 1H).
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH3:8].C=O.NCC1C=CN=CC=1.ClC1C=[C:34](C=CC=1Cl)[CH2:35][N:36](C)[C:37]([C:39]1[CH2:40][N:41](C)[C:42](=O)[C:43]=1O)=O>>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][N:7]([CH3:8])[C:6]([C:5]1[CH:35]([CH3:34])[N:36]([C:37]2[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=2)[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Agent: C=O
Agent: NCc1ccncc1
Product: CC1C(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C(=O)N1c1ccncc1
Yield: 5 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 4-(amino-methyl)pyridine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a sticky orange solid (10.5 mg, 5% yield). 1H NMR (300 MHz, DMSO) δ: 8.75 (d, 2H, J=6.22), 7.63–7.52 (m, 4H), 7.25 (d, 2H, J=7.31), 4.80 (s, 2H), 4.59 (s, 2H), 4.1 (s, 2H), 2.99 (bs, 3H). HRMS (M−H) calcd for C19H16N3Cl2O3: 404.0568. found: 404.0554.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][C:22]=2[OH:36])=[O:19])[CH:15]=[CH:16][CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][C:22]=2[OH:36])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(NC(=O)c2cccc(NC=NN)c2)c(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NN=CNc1cccc(C(=O)Nc2ccc(CCC(=O)O)cc2O)c1
Yield: 41.2 %

Procedure:
The compound of Example 74 (300 mg) was added to methylene chloride (5 mL) followed by the addition of TFA (2 mL). The reaction was monitored by HPLC. After the reaction was complete (2 hours) the product was purified by reverse phase chromatorgraphy (water/acetonitrile) to result in a white solid (110 mg). NMR and MS were consistent with the proposed structure.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].Cl>C(OCC)C>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18](=[NH:3])[NH2:19]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: N#Cc1ccccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: N=C(N)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
According to literature reference (Huang, Y.; Luedtke, R. R.; Freeman, R. A.; Wu, L.; Mach, R. H. Bioorg. Med. Chem. 2001, 9, 3113–3122), to a solution of hexamethyldisilazane (36.7 mL, 175 mmol) in of diethyl ether (300 mL) at 0° C. is added n-butyl lithium (114 mL of 1.6 M solution in hexanes, 182 mmol) and the reaction mixture is stirred at 0° C. for 30 minutes after which time 2-chlorobenzonitrile (10.0 grams, 72.7 mmol) is added and the reaction mixture is warmed to 25° C. and stirred for 5 hours. Once complete, the reaction is poured into 2 N HCl and the aqueous phase was washed twice with diethyl ether. This aqueous phase is then made basic (pH=12) by addition of 6N sodium hydroxide. Subsequently, the aqueous phase is extracted with CH2Cl2 and the combined organic extracts are dried over sodium sulfate and concentrated to provide a crude solid. The crude product is then recrystallized from ethyl acetate to afford 5.4 g of 2-chlorobenzenecarboximidamide.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([OH:14])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][C:17]=1[OH:23].B(F)(F)F.CCOCC>>[Cl:15][C:16]1[C:17]([OH:23])=[CH:18][C:19]([OH:20])=[C:21]([C:12](=[O:14])[CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH:22]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C(O)Cc1ccc2c(c1)OCCO2
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(Cc1ccc2c(c1)OCCO2)c1cc(Cl)c(O)cc1O
Reaction time: 2 h
Yield: 68.4 %

Procedure:
This compounds was synthesised in the same manner as described above. (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-acetic acid (0.3 g, 1.55 mmol), 4-chlororesorcinol (0.22 g, 1.55 mmol), boron trifloride etherate (3 ml). After standing for two hours a precipitate formed which was filtered, washed (water), and dried to give 1-(5-Chloro-2,4-dihydroxy-phenyl)-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone as a white solid (0.34 g, 68.3%); Rf 0.9 hexane/ethyl acetate (20/80).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][SH:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S-:17].[Na+].II.Cl>O.C1COCC1.CCO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][S:17][CH3:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCS)C(=O)O
Agent: Cl
Agent: II
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CSSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 159.3 %

Procedure:
(S)-2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoic acid (Boc-L-Hcs-OH) (188 mg, 0.4 mmol) was dissolved in H2O/THF (50% v/v, 16 mL). To the solution was added sodium thiomethoxide (560 mg, 8.0 mmol) at 0° C. Then, a solution of iodine in 95% EtOH was added dropwise until the color of the reaction system changed from colorless to brown. The mixture was stirred for 1.5 h with warming to room temperature. After removing THF under reduced pressure, reaction mixture was neutralized by 1 N HCl aq. until pH 2-3. The solution was extracted with EtOAc. The extract was washed with saturated NaS2O4 aq. and brine, and dried over MgSO4. Concentration under reduced pressure followed by flash chromatography over silica gel with EtOAc/Hexanes/AcOH (75:25:1) gave Boc-L-Hcm-OH (179.3 mg, 80% yield): 1H NMR (360 MHz, CDCl3) δ 5.06 (s, 1H), 4.44 (s, 1H), 2.78 (t, J=7.7 Hz, 2H), 2.42 (s, 3H), 2.35 (m, 1H), 2.09 (m, 1H), 1.45 (s, 9H); LRMS (ESI) m/z calcd for C10H20NO4S2 (M+H)+ 282.1. found 282.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:31][CH2:32][CH2:33]O)=[C:10]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.CCN(CC)CC.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:31][CH2:32][CH2:33][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[C:10]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: OCCOc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc2c1cnn2-c1ccccc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ccc(-c2c(-c3ccc(Cl)cc3Cl)nc3c(cnn3-c3ccccc3)c2OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy]-ethanol (13 mg, 0.025 mmol, prepared in 84% yield as described in Example 5 except using ethylene glycol as solvent.) in anhydrous CH2Cl2 (0.5 mL) is added CH3SO2Cl (5 μL) followed by Et3N (20 μL). After the addition, the mixture is stirred at room temperature for 2 h. and morpholine (20 μL) is added. After the resulted mixture is stirred at 60° C. for 10 h. it is cooled down to room temperature and treated with water (4 mL) and extracted with EtOAc (3×3 mL). The organic layers are combined and concentrated. The residue is purified by preparative LC/MS to provide the titled compound 5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-(2-morpholin-4-yl-ethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine. HPLC-MS calculated for C30H25Cl3N4O2 (M+H+): 579.1. Found: 579.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14](=[O:31])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[C:18]([Cl:30])[CH:17]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14](=[O:31])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[C:18]([Cl:30])[CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(=O)OC)cc2Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(=O)O)cc2Cl)cc1Cl

Procedure:
A solution of 1.8 g (3.835 mmol) of methyl 3-chloro-4-{[3-chloro-4-(2-diethylamino -ethoxy)-phenylcarbamoyl]-methoxy}-benzoate (from Example 35) and 2 ml of 2 M aqueous NaOH solution in 20 mL MeOH was refluxed for 1 hour. The reaction solution was evaporated down i. vac., diluted with water and acidified weakly with HCl. After 3 days at RT the solution was evaporated down i. vac. The residue was triturated with cold EtOH and the precipitate was filtered off.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=O)[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:22][S:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)(=[O:25])=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]([C:19](=[O:21])[NH:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:29]4[CH2:28][CH2:27][N:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:31][CH2:30]4)=[CH:34][CH:35]=3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(C(=O)O)ccc2Cl)cc1
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2cc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of 6-chloro-biphenyl-3,4′-dicarboxylic acid 4′-ethyl ester (152 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (175 mg), EDAC (125 mg), HOBT (88 mg) and N-methylmorpholine (143 μl) in DMF (3 ml) was stirred at room temperature. After 1 h, water (30 ml) was added and the resulting suspension filtered. The residue was then purified by chromatography. Gradient elution with 30-100% ethyl acetate in petrol gave a beige solid (240 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].[N+:15]([O-])([O-:17])=[O:16].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
2-Cyanobiphenyl (0.111 moles, 20.0 g) and ammonium nitrate (10.0 grams) were added to 250 ml chloroform. Trifluoroacetic anhydride (80 ml) was added. The reaction mixture was stirred until the ammonium nitrate was dissolved. The reaction mixture was added to 300 ml of ice water. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to yield 23.5 g of 2-Cyano-4-nitrobiphenyl. (MS)
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].[F-].[K+].[C:28]([O-:32])(=[O:31])[CH2:29]C.[Na+].ClCC(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([O:25][CH2:29][C:28]([OH:32])=[O:31])=[O:24]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CCC(=O)[O-]
Agent: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
One hundred grams of indomethacin, 91.25 g of potassium fluoride and 13.5 g of sodium propionate were suspended in 500 ml of dimethylformamide, followed by an addition of 64.31 g of t-butyl chloroacetate. The resultant mixture was stirred and then stirred for 1 hour in a water bath of 90° C. After cooling, the mixture was poured into 5 liters of a 10% solution of sodium carbonate in water, followed by an addition of water to make the total volume be 20 liters. The resulting yellowish solid deposit was separated and then taken up in 1.65 liters of benzene. The thus-prepared solution was washed with water and, after drying, the solvent was driven off. The residue was recrystallized from n-hexane, thereby obtaining 126.1 g of the t-butyl ester of acemetacin as pale yellowish crystals (yield: 95.6%)