Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:15]1[CH:16]=[C:17]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH:18]=[N:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:15]2[CH:16]=[C:17]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH3:28])[CH:18]=[N:19][CH:20]=2)[CH:2]=1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2cnc3ccccc3c2)c1

Procedure:
To a solution of the compound from step 35a and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (271 mg, 1.0 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2M solution), and the mixture was heated at reflux for 4 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with 2 to 5% methanol in methylene chloride in a first column, followed by rechromatography, eluting with 0.1 to 1% ether in hexane, to afford 120 mg of the title compound. MS (CI/NH3) m/z 320 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.82, (m, 3H), 2.06 (m, 1H), 2.34 (m, 1H), 2.52 (s, 3H), 2.73 (m, 1H), 3.13 (m, 1H), 4.09 (m, 2H), 7.52 (m, 1H), 7.62, (m, 1H), 7.76 (m, 1H), 7.90 (m, 1H), 8.16 (m, 1H), 8.32 (m, 1H), 8.40 (m, 1H), 8.58 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][N:11]=[C:10]2[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[CH:27]=2)=[O:25])[CH:18]=1)=O.C1COCC1.CC(O)C.[OH-].[NH4+:43]>O>[Cl:32][C:28]1[CH:27]=[C:26]([C:24]([NH:23][C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][NH:15][C:10]2[C:9]3[C:14](=[C:5]([C:3]([NH2:43])=[O:2])[CH:6]=[CH:7][CH:8]=3)[N:13]=[CH:12][N:11]=2)=[O:25])[CH:31]=[CH:30][N:29]=1
Reactant: COC(=O)c1cccc2c(NCc3cccc(NC(=O)c4ccnc(Cl)c4)c3)ncnc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4ccnc(Cl)c4)c3)ncnc12
Reaction time: 8 h
Yield: 55 %

Procedure:
To a 40-mL vial with magnetic stirbar at r.t. was added the 4-{3-[(2-Chloro-pyridine-4-carbonyl)-amino]-benzylamino}-quinazoline-8-carboxylic acid methyl ester (0.6 g, 1.34 mmol, 1 eq.) and THF (6 mL) and 2-propanol (6 mL). An approx. equal volume (i.e.; 6 mL) of concentrated aqueous ammonium hydroxide solution (28-30% soln.) was then added and stirring continued overnight. Water (15 mL) was added to the reaction mixture and a white precipitate immediately began to form. The precipitate was collected and dried thoroughly in vacuo and afforded 314 mg (55% yield). Material was carried on to the next synthetic step without further purification. LCMS (ESI) 433 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Cl[C:11]1[C:12](=[O:26])[NH:13][C:14](=[O:25])[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1.CN1CCCC1=O>Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[C:12](=[O:26])[NH:13][C:14](=[O:25])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=C1NC(=O)C(c2cccc([N+](=O)[O-])c2)=C1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC2=C(c3cccc([N+](=O)[O-])c3)C(=O)NC2=O)cc1Br
Temperature: 200 °C

Procedure:
A mixture of 3-bromo-4-methylaniline (0.220 g, 1.18 mmol), 3-chloro-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (0.100 g, 0.40 mmol) and 1-methyl-2-pyrrolidinone (1.0 mL) was heated in an oil bath at 200° C., for 51 minutes. The mixture was diluted with aqueous hydrochloric acid (5 mL) and extracted with ethyl acetate (5 mL). The combined organic solutions were evaporated and the residue chromatographed on silica gel using dichloromethane as eluent to afford the title compound, a solid, following trituration with dichloromethane-hexane (90:10 v/v).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:22]([CH:25]=[O:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:22]([CH2:25][OH:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C(C)C)nn2c(C=O)ccc2c1-c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(C(C)C)nn2c(CO)ccc2c1-c1ccc(F)cc1
Yield: 88.7 %

Procedure:
A solution of ethyl 4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (100 mg, 0.282 mmol) and sodium borohydride (10.7 mg, 0.282 mmol) in ethanol (1 mL) was stirred for 0.5 h under an ice bath. The mixture was partitioned between ethyl acetate (10 mL) and water (5 mL), and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give ethyl 4-(4-fluorophenyl)-7-hydroxymethyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow gum (89.1 mg, 89.1%).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[CH3:10][S:11](Cl)(=[O:13])=[O:12].N1C=CC=CC=1.Cl>ClCCCl>[CH3:10][S:11]([O:6][CH2:5][C:3]([C:2](=[O:1])[CH3:9])([CH3:4])[CH2:7][O:8][S:11]([CH3:10])(=[O:13])=[O:12])(=[O:13])=[O:12]
Reactant: CC(=O)C(C)(CO)CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(=O)C(C)(COS(C)(=O)=O)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.4 %

Procedure:
66 g (0.5 mol) of 3-oxo-2,2-bis-(hydroxymethyl)butane (for the preparation, see Beilstein H 1, E III 3306, IV 4132 and J. Chem. Soc., London, 1932, 2671) were dissolved in 300 ml of 1,2-dichlorethane, 114.5 g (1 mol) of methanesulphonyl chloride were added dropwise, and 158 g (2 mol) of pyridine were added dropwise at 0°-5° C. The mixture was subsequently stirred at room temperature for 15 hours and then poured onto 600 ml of ice-water and 100 ml of concentrated hydrochloric acid. A solid thereby precipitated and was filtered off. The aqueous phase was extracted with 1,000 ml of methylene chloride; the solid was dissolved in the methylene chloride phase, the organic phase was dried over sodium sulphate, the solvent was distilled off under a waterpump vacuum and the residue was suspended in 200 ml of ether. The residue was filtered off and washed with 100 ml of ether. 100 g (about 70% of theory) of 2-acetyl-2-methyl-propane-1,3-diol bismethanesulphonate of melting point 105°-108° C. were obtained. ##STR71##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16](=[O:24])[CH2:15][CH2:14]1)(=[O:12])=[O:11].[C:25]([O:33][CH2:34][C@H:35](O)[CH2:36][OH:37])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[Si](C)(C)C)(C)C.O>ClCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[C:25]([O:33][CH2:34][C@H:35]1[CH2:36][O:37][C:16]2([CH2:15][CH2:14][CH:13]([S:10](=[O:12])(=[O:11])[NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[O:24]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(OC[C@H](O)CO)c1ccccc1
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: CC(C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OC[C@H](COC(=O)c1ccccc1)O2
Yield: 80.9 %

Procedure:
100 mg (0.27 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 69 mg (0.35 mmol) of (R)-2,3-dihydroxypropyl benzoate were dissolved in 2 ml of dichloromethane and 0.19 ml (1.05 mmol) of isopropoxytrimethylsilane and 2 μl (0.014 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added thereto with stirring under ice-cooling, followed by stirring at the same temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate 1:1), to give 121 mg of ethyl (2R)-2-benzoyloxymethyl-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as a pale yellow oil (yield: 81%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:25]([C:28]([O:30]CC)=[O:29])([CH3:27])[CH3:26])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:35][C:2]([F:1])([F:36])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:25]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:26])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)cc1OC(C)(C)C(=O)O
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A mixture of 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester (156 mg, 0.31 mmol), potassium carbonate (85 mg, 0.62 mmol), methanol (10 mL) and water (2 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 139 mg (94%) of 3-[3-(1-carboxy-1-methyl-ethoxy)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C@@H:19]([OH:22])[CH:20]=[CH:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1.[OH:23][S:24]([OH:27])(=[O:26])=[O:25].CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5C(CC[C@@H]2[C@]5(C=34)CC1)=O.[OH-].[Na+]>CCO.C(#N)C.O>[CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C:19]([CH2:20][CH2:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1)=[O:22].[S:24]([O-:27])([O-:26])(=[O:25])=[O:23]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: O=S(=O)(O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: O=S(=O)([O-])[O-]
Temperature: 81 °C

Procedure:
A reaction flask was charged with codeine base (10.0 g, 33.4 mmol), water (10 mL), and EtOH (20 mL). The reaction mixture was agitated to form a suspension. The reactor was flushed with nitrogen and the reaction mixture was kept under nitrogen throughout the reaction. The reaction flask was charged with H2SO4 (98%, 1.8 mL, 33.4 mmol) and the catalyst (RuCl3.xH2O, 0.20 g). The reaction mixture was heated to reflux (80-82° C.) for 24 h. HPLC analysis indicated that 92% (area) hydrocodone was formed. The reaction mixture was cooled down overnight. Acetonitrile (30 mL) was added to the reaction mixture and the mixture was heated for 1 h. The pH of the reaction mixture was adjusted the pH to 2.5 with 50% NaOH. EtOH (90 mL) was added to the mixture, which as cooled down to 0-5° C. for 1 h. The mixture was filtered, and the solid was washed with 95% EtOH (2×15 mL). The solid was dried under vacuum at 65° C. for 18 h to give 8.32 g of hydrocodone sulfate as solids (purity>99% area).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH2:15]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:22])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(OCc2ccccc2)c1C(=O)O
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A mixture of 3-benzyloxy-phthalic acid dimethyl ester (1.64 g, 5.50 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 1 h and cooled to room temperature. The solvent was removed under vacuum and the residue was dissolved in water (100 mL), washed with CH2Cl2 (2×100 mL) and acidified with 6N HCl to pH 1-2. The precipitate was filtered and washed with water (100 mL) to give 3-benzyloxy-phthalic acid as a white solid (1.10 g, 74% yield); 1H NMR (DMSO-d6) δ 5.20 (s, 2H), 7.29-7.51 (m, 8H), 13.02 (br, 2H).
Reaction SMILES: [C:1](O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O.[C:11]1([CH:19]=[C:17]([OH:18])[CH:16]=[C:14]([OH:15])[CH:13]=1)[OH:12]>>[OH:12][C:11]1[C:19]2[C:1](=[O:9])[C:2]3[C:8](=[CH:7][CH:6]=[CH:5][CH:3]=3)[O:18][C:17]=2[CH:16]=[C:14]([OH:15])[CH:13]=1
Reactant: O=C(O)c1ccccc1O
Reactant: Oc1cc(O)cc(O)c1
Product: O=c1c2ccccc2oc2cc(O)cc(O)c12
Temperature: 80 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
Salicylic acid (1.25 g, 9.1 mmol), phloroglucinol (1.26 g, 10 mmol), ZnCl□(3.1 g, 22.8 mmol) and POCl□ (8 mL) were charged to a dry round-bottom flask, and the reaction mixture was stirred at 80° C. for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and was very slowly added to ice water. When the reaction liquid was poured in ice water, ice was added portionwise to prevent overheating. The resulting precipitate was allowed to stand at 4° C. overnight, combined, washed with water and ether, and then dried under reduced pressure to give a reddish brown solid compound (1.94 g, 93%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](/[C:10](=[CH:16]/[N:17]([CH3:19])C)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1.[NH2:21][CH2:22][CH2:23]C#N>C(O)C.C(OCC)C>[Cl:20][C:4]1[N:3]=[C:2]2[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]2[CH2:19][CH2:23][C:22]#[N:21])=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ccc(Cl)nc1Cl
Reactant: N#CCCN
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cn(CCC#N)c2nc(Cl)ccc2c1=O
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 81A (20 g) and 3-aminopropionitrile (4.9 mL) in 1:1 ethanol/diethyl ether (400 mL) was stirred for 15 minutes, diluted with hexanes (1 L), and filtered. The filtrant was dissolved in acetonitrile (400 mL), and the resulting solution was treated with potassium carbonate (17.4 g), heated at 75° C. for 18 hours then cooled, diluted with water (1.5 L), stirred for 1 hour, and filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[O:17])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (148 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [Prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (245 mg, 0.39 mmol, 75% yield) as a yellow oil: LCMS (ES) m/e 615, 617 (M, M+2)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[S:8][C:7]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([CH2:18][C:19]([O:21]CC)=[O:20])=[CH:17][C:11]=3[N:10]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[S:8][C:7]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([CH2:18][C:19]([OH:21])=[O:20])=[CH:17][C:11]=3[N:10]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3.2 34.7 ml of aqueous 1 N sodium hydroxide solution are added to a solution of 10.1 g (about 20.5 mmol) of ethyl [2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]acetate in 70 ml of methanol, and the mixture is stirred at room temperature for 3 days. The reaction mixture is evaporated, and the residue is taken up in 25 ml of water. A pH of 4.5 is set by addition of conc. hydrochloric acid. The resultant precipitate is filtered off, washed with water and dried, giving [2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]acetic acid as a yellowish solid; ESI 293.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13](=O)[NH:14][C:15]3[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=3[NH2:21])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].[OH-].[K+]>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]3[NH:14][C:15]4[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=4[N:21]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4]
Reactant: CCCn1c(N)c(NC(=O)C23CCC(C(=O)OC)(CC2)CC3)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)OC)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
4-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydropyrimidin-5-ylcarbamoyl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (VII, Example 83a, 1 wt) and isopropanol (4.76 vol) are mixed and stirred under nitrogen. Potassium hydroxide (2M, 4.76 vol) is added. The title compound is formed but not isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:15]=2OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCOC.CC1(C)C(C)(C)OB([C:48]2[CH2:55][CH2:54][C:51]3([CH2:53][CH2:52]3)[CH2:50][CH:49]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:16][C:15]=2[C:48]2[CH2:55][CH2:54][C:51]3([CH2:53][CH2:52]3)[CH2:50][CH:49]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCOCC3)cc2OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)OB(C2=CCC3(CC2)CC3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCOCC3)cc2C2=CCC3(CC2)CC3)CC1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A mixture of 4-(4-morpholin-4-yl-2-trifluoromethanesulfonyloxyphenyl)piperazine-1-carboxylic acid t-butyl ester (1.49 g, 3.01 mmol), 1,2-dimethoxyethane (15 mL), water (1 mL), 4,4,5,5-tetramethyl-2-spiro[2.5]oct-5-en-6-yl-[1,3,2]dioxaborolane (1.13 g, 4.82 mmol) produced in Example (34b), tetrakis(triphenylphosphine)palladium(0) (278 mg, 0.241 mmol) and tripotassium phosphate (1.23 g, 5.78 mmol) was stirred for 13 hours and 20 minutes at an external temperature of 80-90° C. under a nitrogen atmosphere. Ethyl acetate and brine were added to the reaction mixture and extraction was performed three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1.23 g of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1B(O)O.[NH2:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:13]1[N:14]=[C:15]([Cl:20])[CH:16]=[C:17]([C:3]2[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[N:18]=1
Reactant: Cc1ccc(Br)cc1B(O)O
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 80.1 %

Procedure:
To a mixture of 2-methyl-5-bromo-phenylboronic acid (7.0 g, 32.6 mmol), 2-amino-4,6-dichloropyrimidine (6.95 g, 42.4 mmol), and degassed ethylene glycol dimethyl ether (150 ml) was added a solution of sodium carbonate (17.3 g, 163 mmol) in water (50 ml). The mixture was stirred vigorously and palladium acetate (0.73 g, 3.26 mmol) was added followed by triphenylphosphine (1.71 g, 6.52 mmol). After stirring for 16 hours, the mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:4) to provide 2-amino-4-chloro-6-(2-methyl-5-bromo-phenyl)-pyrimidine (7.8 g, 80% yield) as a pale yellow powder. 1H NMR (DMSO-d6) δ 7.58 (d, J=2.0 Hz, 1H), 7.55 (dd, J=2.0, 8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.26 (br s, 2H), 6.86 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]3/[C:13](=[C:23](/[CH3:26])\[C:24]#[N:25])/[C:14]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=4[O:16][CH2:17][C:11]=3[CH:10]=2)=[C:6]([CH2:29][O:30][CH3:31])[N:5]=[C:4]([CH3:32])[N:3]=1.CO.[CH3:35][NH:36][CH3:37]>>[CH3:35][N:36]([CH3:37])[C:2]1[C:7]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]3/[C:13](=[C:23](/[CH3:26])\[C:24]#[N:25])/[C:14]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=4[O:16][CH2:17][C:11]=3[CH:10]=2)=[C:6]([CH2:29][O:30][CH3:31])[N:5]=[C:4]([CH3:32])[N:3]=1
Reactant: CNC
Reactant: COCc1nc(C)nc(Cl)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Solvent: CO
Product: COCc1nc(C)nc(N(C)C)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 57.4 %

Procedure:
[step 4] Using (E)-2-(8-{[4-chloro-6-(methoxymethyl)-2-methylpyrimidin-5-yl]methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (164 mg, 0.365 mmol) obtained in step 3 and 2 mol/L dimethylamine methanol solution (1.28 mL, 2.55 mmol), and in the same manner as in Reference Example 13G, step 4, the title compound (96 mg, 56%) was obtained.