Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[N:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]5C=C[CH:30]=[CH:29][CH:28]=5)=[N:23][CH:24]=4)=[CH:15][N:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[C].[Pd].CO>[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([O:12][C:13]3[N:14]=[CH:15][C:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH:26]5[CH2:27][CH2:28][CH2:29][CH2:30]5)=[N:23][CH:24]=4)=[CH:17][N:18]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(COc2ccc(-c3cnc(OC4CCN(C5CCCC5)CC4)nc3)cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1cc(OC2CCCC2)ncc1-c1cnc(OC2CCN(C3CCCC3)CC2)nc1

Procedure:
10% palladium-carbon (700 mg) was added to a methanol solution (30 ml) of 2-(cyclopentylpiperidin-4-yloxy)-5-(2-benzyloxypyridin-5-yl)pyrimidine (2.22 g), and stirred in a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered to remove palladium-carbon, and the filtrate was concentrated under reduced pressure to obtain the entitled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:33]([CH3:32])[S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(Br)cc2n1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(N(C)S(=O)(=O)c3ccc(C)cc3)cc2n1C(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 37.5 %

Procedure:
Under argon, 340 mg 6-Bromo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester (see example 132), 157 mg N-methyl-para-toluenesulfonamide, 322 mg cesium carbonate, 32 mg Pd2(dba)3, and 30 mg xantphos are dissolved in 6.8 mL toluene. Argon is bubbled through the solution for 5 minutes. The reaction mixture is heated to 130° C. for 1 hour in a microwave oven. Then the reaction mixture is diluted with EtOAc and washed with water. The organic phase is dried (MgSO4) and the solvent removed in vacuo. Purification by HPLC affords 155 mg (37%) 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-[methyl-(toluene-4-sulfonyl)-amino]-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1[N:5]2[C:6]([N:10]3[CH2:14][CH2:13][CH2:12][C@@H:11]3[CH2:15][OH:16])=[CH:7][CH:8]=[N:9][C:4]2=[N:3][CH:2]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>ClCCl>[CH3:24][S:25]([O:16][CH2:15][C@H:11]1[CH2:12][CH2:13][CH2:14][N:10]1[C:6]1[N:5]2[N:1]=[CH:2][N:3]=[C:4]2[N:9]=[CH:8][CH:7]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCCN1c1ccnc2ncnn12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCCN1c1ccnc2ncnn12
Temperature: 0 °C

Procedure:
1.5 g of ((R)-1-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylpyrrolidin-2-yl)methanol are dissolved in 15 ml of dichloromethane with stirring, and 1.9 ml of triethylamine are added. This solution is cooled to 0° C., and a solution of 0.8 ml of methanesulfonyl chloride in 5 ml of dichloromethane is added dropwise. When the addition is complete, the mixture is allowed to warm to RT for 12 h. For workup, the solution is poured into equal proportions by volume of water, the organic phase is extracted to exhaustion with ethyl acetate, the combined organic phases are dried over sodium sulfate, filtered off with suction, evaporated and chromatographed on silica gel, giving 1.1 g of ((R)-1-[1,2,4]triazolo-[1,5-a]pyrimidin-7-ylpyrrolidin-2-yl)methyl methanesulfonate as colourless oil;
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].[O:31]=[C:32]1[CH:36]([CH2:37]OS(C)(=O)=O)[CH2:35][CH2:34][N:33]1[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[O:31]=[C:32]1[CH:36]([CH2:37][N:25]2[CH:26]=[C:22]([C:9]3[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]4[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:30])[N:6]([CH2:27][CH2:28][CH3:29])[C:7]=4[N:8]=3)[CH:23]=[N:24]2)[CH2:35][CH2:34][N:33]1[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:51])([F:50])[F:52])[CH:44]=1
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Reactant: CS(=O)(=O)OCC1CCN(c2cccc(C(F)(F)F)c2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC4CCN(c5cccc(C(F)(F)F)c5)C4=O)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 77.5 °C
Yield: 64.5 %

Procedure:
A mixture of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.23 mmol), methanesulfonic acid 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl ester (0.10 g, 0.32 mmol), K2CO3 (0.045 g, 0.32 mmol) and DMF (1 ml) was heated at 75-80° C. for 16 hrs. Reaction mixture was cooled to 20-25° C. and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate, washed with saturated brine solution. The organic layer was dried over Na2SO4 and evaporated to obtain crude product (0.2 g). The crude product was purified by preparative TLC to obtain pure 8-{1-[2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.10 g, 65%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH:39]1[C:51]2[C:50](=[O:52])[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]=2[CH:42]=[CH:41][CH:40]=1>>[OH:52][C:50]1([C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[C:51]2[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=2[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C1c2ccccc2-c2ccccc21
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C3(O)c4ccccc4-c4ccccc43)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-(9-Hydroxyfluoren-9-yl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 9-fluorenone instead of benzophenone) as a colourless foam.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[N:4]=[C:5]([C:8](OCC)=[O:9])[S:6][CH:7]=1.[BH4-].[Na+]>CO>[F:1][CH:2]([F:13])[C:3]1[N:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C(F)F)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1nc(C(F)F)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of ethyl 4-(difluoromethyl)-1,3-thiazole-2-carboxylate (900 mg) in MeOH (15 ml) was added NaBH4 (329 mg), and the mixture was stirred at room temperature for 2 h. The mixture was partitioned between saturated NH4Cl solution and EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (703 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([CH2:15]O)[CH:12]=[C:11]([CH3:17])[N:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>ClCCl>[Cl:20][CH2:15][C:13]1[CH:12]=[C:11]([CH3:17])[N:10]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:14]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)nc(Nc2ccc(F)cc2)n1
Solvent: ClCCl
Product: Cc1cc(CCl)nc(Nc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At 0° C., 225 mg (0.96 mmol) of the compound from example 6A and 137 mg (1.16 mmol) of thionyl chloride are initially charged in 10 ml of dichloromethane and, after warming to RT, stirred at this temperature for 24 h. The solvent is removed on a rotary evaporator and the product that remains is directly reacted further.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClC(Cl)C>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])(=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1cccc(C(=O)c2ccccc2)c1C
Temperature: 25 °C

Procedure:
To a stirred solution of 2,3-dimethylbenzoyl chloride (35 g, 208 mmol) at 0° in dry dichloroethane (80 ml) was added anhydrous aluminium chloride (27.7 g, 208 mmol) portionwise over two minutes. The mixture was stirred for fifteen minutes and dry benzene (40 ml) was added. After warming to room temperature over fifteen minutes, the mixture was heated to reflux for four hours. The dark solution was cooled, poured onto ice (200 ml) containing concentrated hydrochloric acid (20 ml) and extracted with ether (3×100 ml). The combined organic layers were washed with 10% sodium hydroxide (2×50 ml), 10% sodium carbonate (50 ml) and brine (50 ml). After drying the organic layer over sodium sulphate, the solvent was removed under reduced pressure and the red oil (36 g) so obtained was chromatographed (SiO2 (400 g) using petroleum ether (60°-80°) and chloroform (0-12%) as eluent). This gave the desired 1-benzoyl-2,3 -dimethylbenzene (18.2 g, 42%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:14]1[S:15][CH:16]=[CH:17][N:18]=1.ClCCCl>C(Cl)(Cl)Cl>[C:1]([N:8]1[CH2:11][CH:10]([NH:12][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: Brc1nccs1
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC(Nc2nccs2)C1
Temperature: 140 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
A mixture of 5.0 g (29.1 mmol) of 1-Boc-3-aminoazetidine and 2.62 ml (29.1 mmol) of 2-bromothiazole was heated to 140° C. with stirring for 2 h. After cooling to RT, 800 mg (3.14 mmol, 11%) of 1-Boc-3-(thiazol-2-ylamino)azetidine were obtained from the mixture by CC (SiO2, 1 st DCE, 2nd chloroform).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.[O:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH2:32]>>[CH3:26][C:4]1[N:3]=[C:2]([NH:32][C:28]2[O:27][CH:31]=[CH:30][N:29]=2)[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=1
Reactant: Nc1ncco1
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(Cl)n1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(Nc2ncco2)n1

Procedure:
The title compound is prepared from 2-chloro-6-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (25 mg, 0.06 mmol, Step-1, single enantiomer) and oxazol-2-amine (16 mg, 0.19 mmol) according to the procedure similar to that described in Step-4 of Example 445.
Reaction SMILES: [C:1]12[C:18](=[O:19])O[C:15](=[O:16])[C:13]3=[C:14]1[C:5](=[CH:6][C:7]1[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]=[CH:3][CH:2]=2.[OH-].[NH4+:21]>>[C:15]1(=[O:16])[C:13]2[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][C:1]=3[C:18](=[O:19])[NH:21]1)[CH:6]=[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]1=2
Reactant: [NH4+]
Reactant: O=C1OC(=O)c2c3ccccc3cc3cccc1c23
Agent: [OH-]
Product: O=C1NC(=O)c2c3ccccc3cc3cccc1c23
Yield: 86 %

Procedure:
1.51 g (6 mmol) of anthracene-1,9-dicarboxylic acid anhydride was treated with 10 ml of ammonium hydroxide (28%). After refluxing for 16 hours the solid was collected, washed with water, dried in vacuo, and crystallized from dimethylformamide-water to give 1.3 g (86%) of 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione. M.p. 310° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[CH:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl>[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[CH:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])=[CH:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-amino-phenyl)-amide (40 mg, 0.072 mmol) in methylene chloride (5 mL), acetic anhydride (0.072 mmol) was added at room temperature followed by triethylamine (0.10 mL). The mixture was stirred at for 1 hr. and then chromatographed on an ISCO machine (12 g, 40-85% EtOAc/Hexanes) to give a white solid. 34 mg.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[N:3]=[CH:2]1.[CH3:11][Si](C)(C)Cl>CO>[CH3:11][O:9][C:8](=[O:10])[CH2:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)CCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 3-(1H-Imidazol-4-yl)-propionic acid (700 mg) in MeOH (20 mL) was added trimethyl chlorosilane (2 mL) dropwise. The mixture was stirred for 6 h at RT and concentrated under reduced pressure. The residue was evaporated from MeOH (1×) and from toluene (1×) to give crude 3-(1H-imidazol-4-yl)-propionic acid methyl ester as its hydrochloride salt (950 mg, colorless solid), which was used without further purification in the next step.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:23][N:24]([C:35]([O:37]C3C=CC=CC=3)=O)[O:25]C(OC3C=CC=CC=3)=O)=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:44]>C(O)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:23][N:24]([OH:25])[C:35](=[O:37])[NH2:44])=[N:12]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1ccc(-n2nc(CN(OC(=O)Oc3ccccc3)C(=O)Oc3ccccc3)cc2-c2ccc(Cl)cc2)cc1
Reactant: N
Solvent: CCO
Product: NC(=O)N(O)Cc1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1

Procedure:
The compound from Step 5 (6.0 g, 9.7 mmol) was dissolved in 150 mL of ethanol and the solution was saturated with ammonia. The solution was let stand undisturbed overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1 N HCl and brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo to afford N′-[[1-(4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]methyl]-N′-hydroxyurea as a white solid that was crystallized from a mixture of ethyl acetate and hexane: mp 216-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23](F)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:35]3[CH2:40][CH2:39][S:38][CH2:37][CH2:36]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)F)cc2)cc1OC
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)N3CCSCC3)cc2)cc1OC
Temperature: 90 °C
Yield: 65 %

Procedure:
500 mg (0.95 mmol) of 4-((2-(4-chlorophenylsulfonylamino)-4,5-dimethoxybenzoyl)amino)benzenesulfonyl fluoride were dissolved in 1 ml of thiomorpholine and heated at 90° C. for 30 min. For workup, the mixture was poured into 50 ml of ice/1 N hydrochloric acid, and the precipitate was filtered off with suction, dried in a vacuum dryer over phosphorus pentoxide, and recrystallized from hexane/ethyl acetate. 378 mg (65%) of the title compound of melting point 241° C. were obtained.
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[CH3:12][CH:13]([CH3:33])[C:14]([O:16][CH:17]([O:19][C:20]([CH:22]([NH2:32])[C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]1)=[O:21])[CH3:18])=[O:15].C(=O)(O)[O-].[Na+:38].C(#N)C>O>[CH3:12][CH:13]([CH3:33])[C:14]([O:16][CH:17]([O:19][C:20]([CH:22]([NH2:32])[C@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]([O-:31])=[O:30])[CH2:27][CH2:28]1)=[O:21])[CH3:18])=[O:15].[Na+:38]
Reactant: CC(OC(=O)C(C)C)OC(=O)C(N)[C@H]1CC[C@H](C(=O)O)CC1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(OC(=O)C(C)C)OC(=O)C(N)[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Following the general procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 5.03 g (15.94 mmol) of trans-4-{[1-(2-methylpropanoyloxy)ethoxycarbonyl]-aminomethyl}-cyclohexanecarboxylic acid 13 was reacted with 1.34 g (15.94 mmol) of sodium bicarbonate (NaHCO3) in 40 mL of a mixture of acetonitrile and water (1:1) to yield 5.38 g (quant.) of the title compound 14 as a colorless powder. 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.84 (br. m, 2H), 1.057 (d, J=6.4 Hz, 3H), 1.059 (d, J=6.8 Hz, 3H), 1.20-1.32 (br. m, 3H), 1.38 (d, J=5.2 Hz, 3H), 1.59-1.73 (br. m, 3H), 1.75-1.83 (m, 2H), 2.43-2.53 (m, 1H), 2.72-2.84 (br. m, 2H), 6.62 (q, J=5.6 Hz, 1H), 7.42 (t, J=5.6 Hz, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(F)cc2)CC(C)(C)C1
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OCCOCCO)cc2)CC(C)(C)C1
Yield: 44.5 %

Procedure:
The O-alkylation procedure described for 10 (Example 5, step 2) was followed using 9 (339 mg, 1 mmol), K2CO3 (414 mg, 3 mmol), 2-[(2-chloroethyl)oxy]ethanol (0.63 mL, 6 mmol), and acetone (30 mL). The reaction mixture was refluxed for 60 h. The reaction mixture was filtered, concentrated, and purified by column chromatography to give 190 mg (45%) of the title product 24 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.16-7.13 (m, 2H), 7.11-7.07 (m, 2H), 7.0 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.59 (t, J=5.2 Hz, 2H), 4.03 (t, J=4.8 Hz, 2H), 3.70 (t, J=4.4 Hz, 2H), 3.49-3.44 (m, 4H), 1.90 (s, 2H), 1.86 (s, 2H), 1.24 (s, 2H), 0.87 (s, 6H), 0.87 (s, 6H). LCMS (APCI): m/z 427 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:28]=[CH:27][C:16]2[N:17]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18](=[O:21])[N:19]([CH3:20])[C:15]=2[C:14]=1[F:29])(=O)=O.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][N:17]1[C:16]2[CH:27]=[CH:28][C:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:14]([F:29])[C:15]=2[N:19]([CH3:20])[C:18]1=[O:21]
Reactant: OB(O)c1ccccc1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3ccccc3)c(F)c21
Reaction time: 0.25 h

Procedure:
A solution of Cesium carbonate was treated with a solution of 1-(2,2-dimethylpropyl)-4-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl trifluoromethanesulfonate (7-7, 80 mg, 0.21 mmol) and Phenylboronic acid (50.8 mg, 0.42 mmol, 2.0 eq) in anhydrous THF (5 ml). The mixture was deoxygenated, and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex was introduced (8.5 mg, 10.4 μmol, 0.05 eq) and the mixture was irradiated in a microwave at 140 deg C. for 15 min. The reaction was not complete, so more Phenylboronic acid (26 mg, 0.24 mmol, 1.0 eq) and catalyst (8.5 mg, 10.4 μmol, 0.05 eq) was added and the reaction was irradiated again at 170 deg C. for 25 min. LC/MS showed complete conversion, so the crude maroon oil was partitioned between EtOAc (2×45 ml) and aqueous saturated NaHCO3 (55 ml), the combined organic layers were dried over Na2SO4 and concentrated, then purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present). The title compound, 1-(2,2-dimethylpropyl)-4-fluoro-3-methyl-5-phenyl-1,3-dihydro-2H-benzimidazol-2-one (7-8), was obtained as a brown oil with >95% purity. 1H NMR (500 MHz, CDCl3) δ 7.54-7.52 (m, 2H), 7.45 (t, 2H, J=5.86 Hz), 7.38-7.35 (m, 1H), 7.09 (t, 1H, J=5.38 Hz), 6.89 (d, 1H, J=6.35 Hz), 3.69 (s, 2H), 3.66 (s, 3H), 1.06 (s, 9H). LRMS m/z: Calc'd for C19H21FN2O (M+H) 313.4, found 313.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([OH:27])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:25])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:26])[C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:28]([O-:34])(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].[Na+]>CC(C)=O>[C:28]([O:34][CH2:2][C:3]([C:5]1([OH:27])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:25])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:26])[C:8]=2[CH2:7][CH2:6]1)=[O:4])(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C1c2ccccc2C(=O)c2c(O)c3c(c(O)c21)CCC(O)(C(=O)CBr)C3
Reactant: CCCCC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCC(=O)OCC(=O)C1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Temperature: 25 °C

Procedure:
A mixture of 9-bromoacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (1.00 g) obtained in Reference Example 1-(1), sodium valerate (1.44 g) and acetone (50 ml) was stirred under reflux for 5 hours, cooled to room temperature and concentrated under reduced pressure. The residue was triturated with an adequate quantity of ether, and solid substances were filtered to give reddish crystals of 9-valeryloxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 170°-172° C.