Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[C:38]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:37]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:39]4[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][C:38]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1cc(Cl)ccc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4ccc(Cl)cc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.4 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.200 g, 0.342 mmol) and (S)-(4-chloro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.093 g, 0.411 mmol) in DMF (1 mL) was added sodium hydride (0.021 g, 0.513 mmol) and the mixture was stirred at rt. After 2 h, the mixture was diluted with EtOAc and washed with water and brine. The organic phase was concentrated and purified by prep-HPLC to afford (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((4-chloro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (41.4 mg, 0.063 mmol, 18.47% yield) as an amber glass. LCMS (M+H) calcd for C35H48ClN4O6: 655.32. found: 655.5.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([C:16]1[C:24]([F:25])=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18](Cl)[N:17]=1)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([C:16]1[C:24]([F:25])=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18]([O:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[N:17]=1)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: NC(=O)c1cc(F)c(C2CC3CCC(C2)N3Cc2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)c(C2CC3CCC(C2)N3Cc2ccccc2)nc1Oc1ccc(F)cc1
Yield: 66.7 %

Procedure:
Exo-N-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl-2-chloro-5-fluoro-nicotinamide (7.9 g, 21 mmol) (see Preparation 33), 4-fluorophenol (2.6 g, 23 mmol) and caesium carbonate (13.8 g, 42 mmol) were stirred in N,N-dimethylformamide (200 ml) at 70° C. under an atmosphere of nitrogen for 20 hours. The reaction mixture was then partitioned between ethyl acetate (300 ml) and water (300 ml) and the organic layer separated. The organic phase was then washed with a saturated aqueous solution of sodium chloride (3-fold 200 ml), concentrated in vacuo and the residue purified by flash column chromatography on silica gel eluting with a solvent gradient of 20:80 changing to 100:0, by volume, ethyl acetate:pentane. The product was triturated with pentane (30 ml) giving exo-N-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide (6.3 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)[CH3:34].ON1C2C=CC=CC=2N=N1.C(N)C>O.CN(C)C=O>[CH2:33]([NH:35][C:18](=[O:19])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1)[CH3:34]
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min, and then ethylamine (2M solution in tetrahydrofuran, 0.43 mL) was added to the mixture. The whole was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residual crystals were washed with ethyl acetate-hexane and collected by filtration to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (130 mg, 62%) as colorless prisms. MS 489 (MH+). mp 236-237° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])=[N:8][C:9]([CH3:18])=[CH:10][C:11]=1[O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:14]([CH:13]([O:12][C:11]1[C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:19]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[C:7]=2[N:8]=[C:9]([CH3:18])[CH:10]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1NC(=O)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc2c1NC(=O)CN2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a cooled solution of 2-chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-acetamide (40 mg, 0.099 mmol) in dry THF was added 1.0 M lithium bistrimethylsilyl amide (LiN(SiMe3)2) in THF (0.3 ml, 0.3 mmol) at −78° C. and stirred at that temperature for 1 hour, then warmed to room temperature for 30 min. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 38 mg of the title compound as a tan crystals. The crystals were purified through silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give 29 mg (81%) of the title compound as a white crystal, mp 179-181° C. 1H NMR (CDCl3) δ 7.75(s,1H), 6.95(s,2H), 6.09(s,1H), 4.22(s,2H), 4.22(m,1H), 2.32(s,3H), 2.17(s,3H), 2.16(s,6H), 1.71(m,4H), 0.97(m,6H)ppm.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=3)(=[O:20])=[O:19])[C:14]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:13]([O:37][CH3:38])[N:12]=2)[CH:8]=[CH:7][N:6]=1)C=C.[BH4-].[Na+].Cl>C1COCC1>[OH:4][C:5]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=3)(=[O:20])=[O:19])[C:14]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:13]([O:37][CH3:38])[N:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: C=CCOc1cc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(O)c2)nc1OC
Reaction time: 2 h

Procedure:
60 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-allyloxy-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, product of example 39, were suspended in THF (5 ml), treated at RT with 2.2 mg of tetrakis-(triphenylphosphine)palladium and stirred for 5 minutes after which time 6.4 mg of NaBH4 were added. The mixture was stirred for 2 h until the reaction was completed according to TLC analysis. The reaction mixture was poured into cold diluted HCl, the product extracted into AcOEt. The organic layer was dried over NaSO4 and the solvent removed in vacuo to give 5-methyl-pyridine-2-sulfonic acid [2-(2-hydroxy-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as a light yellow solid. ISN mass spectrum, m/e 494.1 (M−1 calculated for C23H21N5O6S: 494).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N:31]1[C:40]2[C:35](=[N:36][CH:37]=[CH:38][CH:39]=2)[C:34]([S:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)=[CH:33][CH:32]=1>C(O)(C)(C)C>[N:31]1[C:40]2[C:35](=[N:36][CH:37]=[CH:38][CH:39]=2)[C:34]([S:41][C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)=[N:4][N:3]=3)=[CH:44][CH:43]=2)=[CH:33][CH:32]=1
Reactant: Clc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: Nc1ccc(Sc2ccnc3cccnc23)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)(C)O
Product: Clc1ccc(-c2nnc(Nc3ccc(Sc4ccnc5cccnc45)cc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1-Chloro-4-(4-chlorophenyl)phthalazine (30 mg, 109 μmol), p-toluenesulfonic acid monohydrate (10 mg, 55 μmol) and 4-(1,5-naphthyridin-4-ylthio)benzenamine (33 mg, 131 μmol) were combined in t-butanol in a sealed tube and the reaction mixture was stirred at 100° C. for 2 h. The mixture was concentrated in vacuo and the crude material was purified by silica gel chromatography (0 to 100% 90/10/1 CH2Cl2/MeOH/NH4OH) in CH2Cl2. The material was further purified by silica gel chromatography (0 to 100% EtOAc/hexane) to afford N-(4-(1,5-naphthyridin-4-ylthio)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine. MS [M+H]=492; Calc'd 491.99 for C28H18ClN5S.
Reaction SMILES: C([N:8]([CH3:33])[CH:9]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]2[C:23](=[O:32])[C:24]([OH:31])=[C:25]([C:27](OC)=[O:28])[N:26]=[C:10]12)C1C=CC=CC=1.Cl.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][C:37]=1[CH3:44]>CO.[Pd]>[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:27]([C:25]2[N:26]=[C:10]3[CH:9]([NH:8][CH3:33])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13][CH2:12][N:11]3[C:23](=[O:32])[C:24]=2[OH:31])=[O:28])=[CH:38][C:37]=1[CH3:44]
Reactant: Cc1cc(CN)ccc1F
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCN(C(=O)OC(C)(C)C)CC2N(C)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC1CN(C(=O)OC(C)(C)C)CCn2c1nc(C(=O)NCc1ccc(F)c(C)c1)c(O)c2=O
Temperature: 25 °C

Procedure:
8-tert-butyl 2-methyl 10-[benzyl(methyl)amino]-3-hydroxy-4-oxo-6,7,9,10-tetrahydropyrimido[1,2-d][1,4]diazepine-2,8(4H)-dicarboxylate prepared as described in Step 4, was dissolved in MeOH, treated with 1 N HCl (1 eq.) and stirred overnight under an H2 atmosphere in the presence of 10% Pd/C. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. MS (ES) C16H24N4O6 requires 368. Found: 369 (M+H+). The crude organic product was taken in methanol and treated with 1.2 eq. of 4-fluoro-3-methyl-benzylamine and resulting mixture was refluxed overnight. After cooling to room temperature, evaporation of volatiles under reduced pressure yielded title product which was directly taken in the next step. MS (ES) C23H30FN5O5 requires 475. Found: 476 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@H:11]2[CH2:13][O:12]2)=[CH:5][C:4]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32]>C(O)(C)C.C(N)(C)C>[CH:15]([N:14]([CH:10]([CH3:11])[CH3:9])[CH2:13][C@@H:11]([C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:9][C@H:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[C:4]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:5]=1)[CH:22]([CH3:24])[CH3:23])[OH:12])=[O:16]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Solvent: CC(C)O
Solvent: CC(C)N
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN(C=O)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.030 g of tert-butyl {3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methyl-1(S)-(R)-oxiranylpentyl}carbamate (Example 1b) in 1.0 ml of isopropanol and 0.165 ml of isopropylamine is stirred at 60° C. over 2 hours. The reaction mixture is concentrated by evaporation to dryness. The residue is dissolved in 1.22 ml of dichloromethane, admixed successively with 0.006 ml of pyridine and 0.013 g of 4-nitrophenyl formate and stirred at room temperature over 1 hour. The reaction solution is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with 1M HCl, water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.51 (95:5 dichloromethane-methanol).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:33])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[CH2:29]([N:26]([CH2:27][CH3:28])[S:25]([C:22]1[CH:23]=[CH:24][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:33])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:34])=[O:5])[C:17]=2[CH3:18])=[CH:20][CH:21]=1)(=[O:31])=[O:32])[CH3:30]
Reactant: CCN(CC)S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)OC)cc3ccc(F)cc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCN(CC)S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)O)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
Lithium hydroxide monohydrate (0.020 g, 0.45 mmol) was added to a stirred solution of [4-(4-diethylsulfamoyl-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.05 g, 0.11 mmol) in a 3:1 mixture of THF—H2O mixture (6 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave [4-(4-diethylsulfamoyl-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid (0.042 g, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s, 1 H), 8.01 (dd, J=9.20, 6.20 Hz, 1 H), 7.97 (d, J=8.31 Hz, 2 H), 7.91 (s, 1 H), 7.48 (d, J=8.31 Hz, 2 H), 7.39 (td, J=8.80, 2.40 Hz, 1 H), 6.68 (dd, J=11.00, 2.40 Hz, 1 H), 3.85 (s, 2 H), 3.28 (q, J=7.10 Hz, 4 H), 2.07 (s, 3 H), 1.09 (t, J=7.09 Hz, 6 H). MS calcd. for C23H23FNO4S [(M−H)−] 428, obsd. 428.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6]/[C:5]/2=[CH:15]\[C:16]([OH:18])=[O:17].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:8][CH2:9][CH2:10]1)[CH2:6][CH:5]2[CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CC1CC2(CCC2)Oc2ccc(Cl)cc21
Yield: 97.3 %

Procedure:
To a stirred solution of (2E)-(6-chlorospiro[chromene-2,1′-cyclobutan]-4(3H)-ylidene)acetic acid (2.5 g, 9.444 mmol) in ethyl acetate (25 ml) was added 10% Pd/C (50 mg) at room temperature. The reaction mixture was stirred for 12 h at 40 psi hydrogen pressure in Paar hydrogenation apparatus. The reaction mixture was filtered through a celite bed, the filtrate was dried (Na2SO4) and concentrated to give 2.45 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.68-1.78 (m, 5H), 1.86-1.96 (m, 1H), 2.09-2.21 (m, 2H), 2.29-2.38 (m, 1H), 2.99 (d, J=13.2 Hz, 1H), 3.44 (br s, 1H), 6.73 (d, J=8.1 Hz, 1H), 7.04 (d, J=9.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC(C2N(C(C3CCCCC3)[C:53](NC3C=CC(C(O)=O)=CC=3)=[O:54])C3C=C(F)C(F)=CC=3N=2)=CC=1.COC(=O)C1C=CC(N)=C(OC)C=1>N1C=CC=CC=1>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:7]([O:54][CH3:53])[CH:6]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: O=C(O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: COC(=O)c1ccc(N)c(OC)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(OC)c1
Yield: 74 %

Procedure:
This compound was synthesized in analogy to example 20, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 22, intermediate c), 4-amino-3-methoxy-benzoic acid methyl ester and using pyridine as a base to afford the title compound as a colorless solid (74%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)=[CH:27][CH:26]=3)[CH2:16][CH2:15][C:14]2=[O:48])=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:56](OC(=O)C)(=[O:58])[CH3:57]>ClCCl.CN(C)C1C=CN=CC=1>[C:56]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)=[CH:27][CH:26]=3)[CH2:16][CH2:15][C:14]2=[O:48])=[O:11])[CH2:6][CH2:5]1)(=[O:58])[CH3:57]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC(=O)N4CCN(CCO)CC4)c4ccccc43)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCN1CCN(C(=O)CN2C(=O)CCN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccc(C)cc4)cc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.1 %

Procedure:
To a solution of 1-[[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl}-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (178 mg) and triethylamine (31 mg) in dichloromethane (4 ml) was added acetic anhydride (31 mg) and the mixture was stirred at ambient temperature for 1.5 hours. To the mixture was added 4-dimethylaminopyridine (10 mg) and acetic anhydride (10 mg), and then the mixture was stirred at ambient temperature for 15 minutes. The resulting mixture was diluted with dichloromethane and the organic layer was washed successively with saturated aqueous sodium bicarbonate solution and brine. Drying, filtering and the removal of solvents afforded a crude product. The crude product was triturated with a mixture of diethyl ether and n-hexane (1:1) to give 1-{[4-(2-acetoxyethyl)-1-piperazinyl]-carbonylmethyl)-5-{4-[2-(4-methylphenyl)benzoylamino]-benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (205 mg) as a slightly-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl-].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](O)=[O:19])[CH3:14]>C1C=CC=CC=1>[CH2:13]([O:15][C:16]([CH2:17][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:18](=[O:19])[CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:21])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])=[O:19])=[O:21])[CH3:14]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)O
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)Nc1ccc(NC(=O)CC(=O)OCC)c([N+](=O)[O-])c1

Procedure:
15.3 gm (0.1 mol) of 1,4-diamino-2-nitrobenzene were heated in 160 ml of absolute benzene together with 30.1 gm (0.2 mol) of malonic acid monoethylester chloride for 31/2 hours at refluxing. After cooling the precipitate was suctioned off and recrystallized twice from isopropanol. The product had a melting point of 96°-97°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][NH2:17].O>CO>[NH:16]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[NH2:17]
Reactant: NN
Reactant: COC(=O)CCCNC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC(=O)NN
Temperature: 65 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a solution of methyl 4-(tert-butoxycarbonylamino)butanoate (21.0 g, 96.8 mmol) in MeOH (180 mL) was added NH2NH2.H2O (28.0 g, 483 mmol) at rt. The mixture was stirred at 65° C. for 12 hrs then concentrated under reduced pressure. The crude material was dissolved in DCM (400 mL). The organic layer was washed with water (2×), and saturated sodium chloride (2×), dried over Na2SO4, and concentrated to afford tert-butyl 4-hydrazinyl-4-oxobutylcarbamate (18.9 g, 90%) as a white solid. ESI-MS (EI+, m/z): 240 [M+Na]+.
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=O)[O].[K+].[K+].[OH:13][C:14]1[C:19]([CH3:20])=[C:18]([CH3:21])[CH:17]=[C:16]([CH3:22])[C:15]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].[OH2:31].Cl>[OH-].[Na+]>[CH3:20][C:19]1[C:14](=[O:13])[C:15]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:16]([CH3:22])[C:17](=[O:31])[C:18]=1[CH3:21]
Reactant: O
Reactant: Cc1cc(C)c(CCCCCC(=O)O)c(O)c1C
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: CC1=C(C)C(=O)C(CCCCCC(=O)O)=C(C)C1=O
Temperature: 0 °C

Procedure:
Potassium nitrosodisulfonate (0.9 part) was added to a solution of 6-(2'-hydroxy-3',4',6'-trimethylphenyl)-hexanoic acid (formula II-2 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.111 part) in 1% sodium hydroxide (5 volume parts) and water (3 volume parts) and the mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was cooled to 0° C. and, following the addition of cold water (50 volume parts), it was rendered acidic with dilute hydrochloric acid, whereupon a yellow precipitate was obtained. Recrystallization of this precipitate from hexane-ethyl acetate (10:1) provided 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the free form) (0.11 part) as yellow needles melting at 81°-82° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.N1C=CC=CC=1.S(Cl)([Cl:19])=O>C(OCC)C>[CH3:1][C:2]1[S:3][C:4]([C:8]([Cl:19])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(C)c(C(=O)O)s1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1nc(C)c(C(=O)Cl)s1
Yield: 41 %

Procedure:
15.7 g (0.1 mole) of 2,4-dimethylthiazole-5-carboxylic acid were suspended in 300 ml of ethyl ether and 8 g (0.1 mole) of pyridine, followed by the dropwise addition of 12 g (0.1 mole) of thionyl chloride at -3° C. for 45 minutes. After completion of the reaction, filtration and concentrating were conducted to obtain 7.2 g pf 2.4-dimethylthiazole-5-carboxylic acid chloride. Its purity and yield were 85% and 35%, respectively.