Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.[Cl:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[C:76]([CH3:78])([CH3:77])[CH2:75][N:74]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:73][CH:72]=2)=[CH:67][CH:66]=1.S([O-])([O-])=O.[Na+].[Na+].C(O)(C)(C)C.[OH2:97]>>[Cl:64][C:65]1[CH:70]=[CH:69][C:68]([C@:71]2([OH:22])[C@@H:72]([OH:97])[CH2:73][N:74]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:75][C:76]2([CH3:77])[CH3:78])=[CH:67][CH:66]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)C(C)(C)C1
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1C[C@H](O)[C@@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 0 °C
Reaction time: 192 h
Yield: 35.5 %

Procedure:
The title compound was prepared via the method of Sharpless, et. al., J. Org. Chem. 57, 1992, 2768. A stirring suspension of AD-MIX-alpha (2.3 g, 1.554 mmol) and methanesulfonamide (148 mg, 1.554 mmol) in 1:1 tert-butanol/water (16 mL) was cooled to 0° C., then treated with tert-butyl 4-(4-chlorophenyl)-5,5-dimethyl-5,6-dihydropyridine-1(2H)-carboxylate (500 mg, 1.554 mmol). The mixture was allowed to come to room temperature, and stirred for 8 days. The reaction was treated with sodium sulfite (3 g), stirred for 30 minutes, then extracted 3× with ethyl acetate. The combined organic phases were washed 3× with 1M NaOH, once with water, and once with brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with ethyl acetate/hexanes (10%-20%-50% EtOAc) to yield the title compound (196 mg, 0.551 mmol, 35.5% yield) as a colorless foam. MS (ESI+)=378.26, (M+Na)+.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C.C(Cl)Cl>[CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([Cl:24])=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 21-3 (0.307 g, 1.1 mmol) and DMF (1 drop) in methylene chloride (3 ml) under nitrogen cooled in an ice-bath was added dropwise a solution of oxalyl chloride (0.113 ml, 1.3 mmol) in methylene chloride (1 ml). The resulting solution was stirred 1 h with ice-bath cooling, 1 h at ambient temperature, then was evaporated at reduced pressure to give crude 4-(cyclohexylmethyloxy)-3-nitrobenzoyl chloride as an oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:23])[N:4]([CH:20]([CH3:22])[CH3:21])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19].C(O)C.[H][H]>[C].[Pd].C(N(CC)CC)C>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[CH:6]=[N:5][N:4]([CH:20]([CH3:22])[CH3:21])[C:3](=[O:23])[CH:2]=1
Reactant: [H][H]
Reactant: COc1ccc(CNc2cnn(C(C)C)c(=O)c2Cl)c(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cnn(C(C)C)c(=O)c2)c(OC)c1

Procedure:
320 mg of 4-chloro-5-(2,4-dimethoxybenzylamino)-2-i-propyl-3(2H)pyridazinone (Compound No. 97), 50 ml of ethanol, 1 ml of triethylamine and 100 mg of palladium-carbon were stirred, and hydrogen was added to the mixture at a temperature of from 40° to 50° C. for 3 hours. The reaction mixture was filtered, and the filtrate was evaporated. The crude crystals thereby obtained were recrystallized from ethyl ether to obtain 230 mg of the above identified compound having a melting point of from 167 to 168° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][NH:3]1.C1C=CC2N(O)N=NC=2C=1.[CH3:27][CH2:28][N:29]=[C:30]=[N:31][CH2:32][CH2:33][CH2:34]N(C)C.Cl.Cl.Cl.[F:41][C:42]1[CH:43]=[C:44]([NH:69]C(NC(=O)CC2C=CC(F)=CC=2)=S)[CH:45]=[CH:46][C:47]=1[O:48][C:49]1C2=C(C)C(OCCN3CCN(C)CC3)=CN2N=CN=1>CN(C=O)C>[NH:31]1[C:30]2=[N:29][CH:28]=[CH:27][C:49]([O:48][C:47]3[CH:46]=[CH:45][C:44]([NH:69][C:8]([C:7]4[C:2](=[O:1])[NH:3][CH:4]=[C:5]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH:6]=4)=[O:10])=[CH:43][C:42]=3[F:41])=[C:34]2[CH:33]=[CH:32]1
Reactant: O=C(O)c1cc(-c2ccccc2)c[nH]c1=O
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1)c1cc(-c2ccccc2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of 2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxylic acid (35 mg, 0.16 mmol), HOBT (25 mg), and EDCI.HCl (80 mg, 0.42 mmol) in DMF (3.0 mL) at room temperature was added 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (30 mg, 0.12 mmol, Compound B of Example 132). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired product (12 mg, 13%) as a light brown solid. 1H NMR (CD3OD) δ 8.81 (d, 1H, J=2.8 Hz), 8.17 (d, 1H, J=6.6 Hz), 8.00 (dd, 1H, J=12.6, 2.2 Hz), 7.94 (d, 1H, J=3.3 Hz), 7.52-7.27 (m, 7H), 6.80 (d, 1H, J=9.3 Hz), 6.72 (d, 1H, J=6.6 Hz), 6.54 (d, 1H, J=3.8 Hz); MS(ESI') m/z 441.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([CH3:9])=[C:6]([Cl:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][Br:11])=[C:4]([Cl:10])[CH:3]=1
Reactant: Cc1c(Cl)cc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)cc(Cl)c1CBr
Yield: 87.8 %

Procedure:
Heat to reflux a solution of 5-bromo-1,3-dichloro-2-methylbenzene (97 mg, 0.40 mmol), N-bromosuccinimide (76 mg, 0.425 mmol) and benzoyl peroxide (16 mg, 0.06 mmol) in CCl4 (5 mL) for 3 hours under N2. Cool the reaction to room temperature and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 112 mg (87%) of the product as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:16]([N:18]([CH3:22])[C:19](Cl)=[O:20])[CH3:17]>>[CH3:22][N:18]([CH2:16][CH3:17])[C:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[CH2:9]2)=[CH:4][CH:3]=1)=[O:20]
Reactant: Oc1ccc2c(c1)CN(CC1CC1)CC2
Reactant: CCN(C)C(=O)Cl
Product: CCN(C)C(=O)Oc1ccc2c(c1)CN(CC1CC1)CC2
Yield: 50 %

Procedure:
7-Hydroxy-N-cyclopropylmethyl-1,2,3,4-tetrahydroisoquinoline (9) was mixed homogeneously with N-ethyl-N-methyl-carbamoyl chloride (10a) and carried out step (f-2). Purified on a silica gel column (DCM/MeOH=10:1) gave cyclopropylmethyl- and N-Ethyl-N-methyl amino-containing 7-(N-Methyl-N-ethyl-carbamoyloxy)-N-cyclopropylmethyl-1,2,3,4-tetrahydroisoquinoline (12a) (Yield 50%). 1H NMR (300 MHz, CDCl3) (NMR, Varian Gemini): δ 7.06 (d, J=8 Hz, 1H, Aryl H); 6.84 (s, 1H, Aryl H); 6.81 (s, 1H, Aryl H): 3.71 (s, 2H, Ph-CH2—N); δ 3.44, 3.39 (dd, J=7 Hz, 2H, CH3—N—CH2CH3); 3.03-2.75 (m, 7H, CH3—N—CH2—CH3, Ph-CH2—CH2—N); 2.42 (d, J=6 Hz, 2H, N—CH2); 1.24-1.17 (m, 3H, —CH3); 1.14-0.94 (q, J=7 Hz, 1H); 0.58-0.52 (m, 2H); 0.19-0.14 (m, 2H); IR (KBr): ν cm−1=2924, 1715. Fast Atom Bombardment Mass Spectrometry (FABMS) m/z: 289 (M+1) (C17H24N2O2).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=[O:21])[CH2:9]1)C1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=[O:21])[CH2:9]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc2c(c1)CN(Cc1ccccc1)CC(=O)N2
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Temperature: 25 °C
Yield: 92.9 %

Procedure:
To a solution of 4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (4.67 g, 16.5 mmol) in dichloromethane (150 mL) was added benzyl chloroformate (6.2 g, 36.0 mmol). The mixture was heated to reflux for four hours whereupon LCMS showed completion of the reaction. The mixture was cooled to room temperature, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography over silica gel (0-5% MeOH/DCM) to afford 5.0 g (93%) of 7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester; NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.35 (m, 5H), 7.04 (d, J=9 Hz, 1H), 6.84 (d, J=9 Hz, 1H), 5.08 (s, 2H), 4.54 (s, 2H), 4.20 (2s, 2H), 3.70 (2s, 3H); MS (m/e) 327 (M+1); mp 138° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[Cl-].[Al+3].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCc2cc(O)ccc21
Temperature: 25 °C

Procedure:
A suspension of 5-methoxy-1-indanone (10.3 g, 63.5 mmol) in toluene (150 mL) was ice-cooled, and aluminum chloride (16.9 g, 127 mmol) was added by small portions, and the mixture was heated under reflux under nitrogen atmosphere for 4 hr. The reaction mixture was allowed to cool to room temperature and poured into iced water. The organic product was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-hydroxy-1-indanone as yellow crystals.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C@@H:35]([CH3:46])[CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[C@@H:35]([CH3:46])[CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:43])[CH3:42]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CN(C)C(=O)OC(C)(C)C)c(F)c1
Yield: 36 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (180 mg, 0.57 mmol) was reacted with (R)-tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl(methyl)carbamate (150 mg, 0.38 mmol) to afford the desired product (190 mg, 36%) as a yellow solid: ESI MS m/z 511 [C28H31FN2O4S+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5].CC(C)=[O:12].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CO.O>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]([OH:12])=[O:5]
Reactant: CC(C)=O
Reactant: CCCC[C@H](C)CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: CCCC[C@H](C)CC(=O)O
Reaction time: 0.25 h

Procedure:
To 10 g. of 3-(S)-methyl-1-heptanol in 175 ml. of acetone was added over 45 minutes 90 ml. of Jones reagent dropwise at 15°-20° C. After 15 minutes, 15 ml. of isopropanol was added and stirring continued for 30 minutes. The reaction was poured into water and the product extracted with ether. The extracts were combined, washed with water, a sodium bisulfite solution and a brine solution and dried over magnesium sulfate. Removal of the solvent gave 10 g. of the product as a liquid, b.p. 84°-88° C./0.4 torr, [alpha]D =-4.46 (CH3OH C=0.105 g/ml.).
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCCC)(=O)C1C=CC=CC=1.[C:26]([C:34]1[C:42]([N+:43]([O-])=O)=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:43][C:42]1[C:34]([C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:35]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)[CH:36]=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39]
Reactant: O=C(O)c1cc(OCc2ccc(Cl)cc2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: Nc1cc(C(=O)O)cc(OCc2ccc(Cl)cc2)c1C(=O)c1ccccc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 4-benzoyl-3-(p-chlorobenzyloxy)-5-nitrobenzoic acid, and following the procedure described, 5-amino-4-benzoyl-3-(p-chlorobenzyloxy)benzoic acid is obtained with a melting point of 248°-249° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:25])[C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[C:26]([O:33][CH3:34])(=[O:32])[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:25][N:16]([CH2:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:27]([C:26]([O:33][CH3:34])=[O:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:8][CH:7]=2)[CH:14]=[CH:13][CH:12]=1)[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:24]
Reactant: COC(=O)CC(=O)OC
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OC

Procedure:
1.4 g (4.25 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)-N-methylbenzamide (prepared as in Example 1(e)), 20 ml of toluene, 560 mg (4.25 mmol) of dimethyl malonate and 125 mg (0.85 mmol) of piperidine acetate are introduced into a three-necked flask under a stream of nitrogen. The mixture is refluxed for 6 hours, while separating out the water formed using Dean-Stark apparatus. The reaction medium is cooled, extracted with ethyl acetate and washed with water. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The crude product is purified by chromatography on a column of silica eluted with admixture of heptane and ethyl acetate (70/30). After evaporation of the solvents, 1.4 g (75%) of the expected product are collected.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=2)=[CH:4][C:5]([C@@:9]2([CH2:48][CH2:49][CH2:50][OH:51])[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[C:6](O)[CH:7]=1.N1C=CC=CC=1.CS(OS(C)(=O)=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:16]([O:15][C@@H:14]1[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:12]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:10][C@@:9]21[CH2:48][CH2:49][CH2:50][O:51][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=3)=[CH:4][C:5]2=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCc1ccc(Cc2cc([C@]3(CCCO)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)OCCC[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 35 (115 mg, 0.139 mmol) and pyridine (100 μL) in DCM (1 mL) was added methanesulfonic anhydride (44 mg, 0.25 mmol, 1.8 equiv). The resulting mixture was stirred at ambient temperature for 1 hour. LC/MS analysis indicated complete conversion of 35 to mono mesic ester 36. The reaction mixture was partitioned between 10% sodium bicarbonate and DCM, after which the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a residue which was heated in DMF (3 mL) containing potassium carbonate (100 mg) at 90° C. for 0.5 hours. The resulting mixture was extracted with DCM, after which the organic layer was separated, dried (Na2SO4), filtered, and evaporated. Preparatory TLC of the residue eluting with 12% ethyl acetate in petroleum ether gave 37 (62 mg, 55% yield). 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.16-7.28 (m, 21H), 7.08-7.11 (m, 2H), 6.98 (m, 4H), 6.97 (s, 1H), 4.81 (d, J=11.1 Hz, 1H), 4.77 (d, J=10.8 Hz, 1H), 4.73 (d, J=10.8 Hz, 1H), 4.47-4.60 (m, 3H), 4.35 (d, J=10.5 Hz, 1H), 4.16-4.24 (m, 1H), 3.70-4.02 (m, 11H), 2.60-2.71 (m, 1H), 2.54 (q, J=7.5 Hz, 2H), 2.02-2.13 (m, 1H), 1.81-1.93 (m, 2H), 1.16 (t, J=7.5 Hz, 3H). LC/MS m/z 832 (M+Na), 810 (M+H).
Reaction SMILES: [CH3:1][N:2](C)[CH2:3]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.CNC.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:37]2[S:38][CH:39]=[C:40]([CH2:42][CH2:43][C:44]([C:46]3[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=3[C:48](O)=[O:49])=[O:45])[N:41]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][CH3:36])[CH3:26]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:37]2[S:38][CH:39]=[C:40]([CH2:42][CH2:43][C:44]([C:46]3[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=3[C:48]([N:2]([CH3:3])[CH3:1])=[O:49])=[O:45])[N:41]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][CH3:36])[CH3:26]
Reactant: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3C(=O)O)cs2)cc1OCC
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3C(=O)N(C)C)cs2)cc1OCC
Reaction time: 2 h
Yield: 59.8 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) (54 mg, 0.29 mmol), 1-hydroxybenzotriazol (HOBT) (43 mg, 0.29 mmol), and a 50% aqueous dimethylamine solution (0.025 ml, 0.29 mmol) were added at room temperature to a solution (2 ml) of 2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzoic acid (100 mg, 0.24 mmol) in DMF, followed by stirring at the same temperature for 2 hours. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated salt solution in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent was distilled off under reduced pressure, to thereby obtain 65 mg (yield: 61%) of 2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}-N,N-dimethylbenzamide as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[BH4-].[Na+].C(OCC)(=O)C.O>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(N)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc(Cl)cc(CO)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.5 g (55.97 mmol) of methyl 2-amino-6-chloropyrimidine-4-carboxylate (prepared according to G. Doyle Daves, Fred Baiocchi, Roland K. Robins, and C. C. Cheng, J. Org. Chem., 26 (1961), 2755-2763) are initially charged in 450 ml of ethanol. 21.17 g (559.74 mmol) of sodium borohydride are added, and the mixture is stirred at room temperature for 2 hours. 500 ml of ethyl acetate and 500 ml of water are added, and the solution is stirred for 30 minutes. The phases are separated and the aqueous phase is extracted three times with ethyl acetate (in each case 100 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated. This gives 7.21 g (85% of theory) of product.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([NH:11][C:12](SC)=[C:13]([C:17]#[N:18])[C:14]([NH2:16])=O)[CH:8]=[CH:9][CH:10]=1)(C)(C)C.[OH2:21].[NH2:22][NH2:23]>CCO>[NH2:18][C:17]1[NH:23][N:22]=[C:12]([NH:11][C:7]2[CH:6]=[CH:5][C:10]([C:13]([CH3:17])([CH3:14])[CH3:12])=[CH:9][CH:8]=2)[C:13]=1[C:14]([NH2:16])=[O:21]
Reactant: CSC(Nc1cccc(C(C)(C)C)c1)=C(C#N)C(N)=O
Reactant: O
Reactant: NN
Solvent: CCO
Product: CC(C)(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Temperature: 75 °C

Procedure:
3-((3-(tert-butyl)phenyl)amino)-2-cyano-3-(methylthio)acrylamide was then suspended in 10 mL EtOH and hydrazine hydrate (124 μL, 1.0 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(tert-butyl)phenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:26])[C:9]([S:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].O>C1COCC1.CO>[CH:1]1([NH:7][C:8](=[O:26])[C:9]([S:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)([CH3:11])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)COc1ccc(SC(C)(C)C(=O)NC2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Sc1ccc(OCC(=O)O)cc1)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl (4-{[2-(cyclohexylamino)-1,1-dimethyl-2-oxoethyl]thio}phenoxy)acetate (prepared as example 72) was dissolved in THF/MeOH and treated with an aq. LiOH/H2O solution. The reaction mixture was stirred at rt for 16 h. The volatiles were removed in-vacuo and the residual aq. solution was acidified to pH=2 with a 1 N HCl solution. EtOAc was added and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated to provide the desired carboxylic acid as a white solid. LCMS: (M+H)+=352.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Na].[Cl:24][C:25]1[CH:41]=[CH:40][C:28]([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]Cl)[CH2:32][CH2:31]2)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:38][CH2:37][CH2:36][N:33]3[CH2:34][CH2:35][N:30]([CH2:29][C:28]4[CH:27]=[CH:26][C:25]([Cl:24])=[CH:41][CH:40]=4)[CH2:31][CH2:32]3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: O=c1cc(OCc2ccccc2)c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2o1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 4-benzyloxy-7-hydroxycoumarin (9.4 g, 0.035 mole) in dry NN-dimethylformamide (35 ml) was added sodium hydride (0.84 g; 0.035 mole) and the mixture stirred for 1 hour at 100° to complete formation of the sodium salt. To this was added a solution of 1-(4-chlorobenzyl)-4-(3-chloropropyl)piperazine (9.3 g; 0.035 mole) in dry NN-dimethylformamide (40 ml) over 1 hour and the resulting mixture stirred for 4 hours at 100°. The precipitated sodium chloride was filtered from the cooled mixture and the filtrate evaporated in vacuo to a red oil which was extracted with dry ether. Concentration of the extracts afforded 13.5 g (74%) of white crystalline material of m.p. (EtOH) 115°-116°, νmax (mull) 1725, 1625, 1610 cm-1. δ (CDCl3) 2.01 (2H, m); 2.48 (10H, m); 3.46 (2H, s); 4.07 (2H, t, J 6 Hz); 5.17 (2H, s); 5.65 (1H, s); 6.80 (2H, s); 7.27 (4H, s); 7.43 (5H, s); 7.72 (1H, d, J 9.6 Hz). (Found; C, 69.23; H, 6.12; Cl, 7.00; N, 5.22; C30H31ClN2O4 requires; C, 69.42; H, 6.02; Cl, 6.83; N, 5.40%).