Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:19][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CI.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1.[Cl-].[NH4+]>[CH:13]1([CH2:19][C:20]([CH3:1])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C(C)CC1CCCCC1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Product: COC(=O)C(C)(C)CC1CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of diisopropylamine (8.9 ml, 63.3 mmol) in 100 ml of anhydrous THF was added dropwise n-butyl lithium (1.59N, 39.8 ml, 63.3 mmol) at -78° C. under argon atmosphere. After the mixture was stirred at -78° C. for 30 minutes, methyl 3-cyclohexyl-2-methylpropionate (7.7829 g, 42.2 mmol) was added dropwise. After the mixture was stirred at -78° C. for 30 minutes, a solution of methyl iodide (3.9 ml, 63.3 mmol) in HMPA (2.2 ml, 12.7 mmol) was added dropwise. After being stirred at -78° C. for 1 hour, the reaction mixture was diluted with an aqueous saturated solution of ammonium chloride. The aqueous mixture was extracted with ether (50 ml×4). Then, the combined ether layers were washed water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled to give a colorless liquid of methyl 3-cyclohexyl-2,2-dimethylpropionate (5.7294 g, yield 52.2%, b.p. 121.5°-123° C./22 mmHg), which was assigned the structure by the following data:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.C[Sn](C)(C)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:29]1[CH:30]=[CH:31][C:26]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]4[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]4)[N:8]=3)=[CH:4][CH:3]=2)=[CH:27][CH:28]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Reactant: C[Sn](C)(C)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC1(C)CC(Nc2nccc(-c3ccc(-c4ccncc4)s3)n2)CC(C)(C)N1
Temperature: 120 °C

Procedure:
[4-(5-Bromo-thiophen-2-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (Step C of Example 5, 100 mg, 0.253 mmol), 4-trimethylstannylpyridine (186 mg, 0.506 mol) and PdCl2(PPh3)2 (18 mg, 0.025 mmol) were dissolved in xylene (5 ml) and heated to 120° C. for 30 minutes. The reaction mixture was poured on 1N-NaOH and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, evaporated to dryness and purified via preparative HPLC to give the title compound as yellow crystals. Yield: 23 mg (23%)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-:21].[Ca+2].O1CCOCC1.O>C1COCC1>[OH:21][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1NC(=O)c1ccc(CO)cc1
Reaction time: 25 h
Yield: 88.3 %

Procedure:
4-Chloromethyl-N-(2-methoxyphenyl)benzamide (500 mg, 1.81 mmol) and precipitated calcium carbonate (970 mg, 9.7 mmol) were suspended in a dioxane-water (1:1) mixture solution (9 ml) and subjected to 25 hours of heating under reflux. After adding THF (25 ml) and filtering off the formed insoluble materials, the organic solvent was removed by evaporation. The thus obtained residue was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried on anhydrous magnesium sulfate. After removing the solvent by evaporation, the resulting colorless solid material was purified by subjecting it to a silica gel column chromatography (ether:hexane=3:1), thereby obtaining 411 mg (88.3%) of the title compound in the form of colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([NH2:15])[CH2:13][NH2:14]>>[ClH:1].[ClH:1].[NH2:14][CH2:13][CH2:12][NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:14][CH2:13][CH2:12][NH2:15])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(Cl)cccc1Cl
Reactant: NCCN
Product: Cl
Product: NCCNc1cccc(NCCN)c1[N+](=O)[O-]

Procedure:
0.16 mole (30 g) of 2,6-dichloronitrobenzene is added to 100 ml of ethylenediamine. The mixture is heated under reflux for 4 hours. The unreacted ethylene diamine is stripped off under vacuum. The expected product is precipitated by adding a 7N solution of hydrochloric acid to the residue obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][NH:5][C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1)=O.Cl.[NH2:26][OH:27].C(OC)(OC)OC>C1COCC1.N1C=CC=CC=1>[OH:27][N:26]=[C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([N:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])[CH2:4][C:3]([O:2][CH3:1])=[O:12])=[O:24])=[CH:18][CH:17]=1)[CH3:13]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: NO
Reactant: C=CCOC(=O)NCC(=O)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: COC(OC)OC
Product: C=CCOC(=O)N(CC(=O)OC)C(=O)Nc1ccc(C(C)=NO)cc1
Reaction time: 3 h

Procedure:
A solution of 0.02 mol N-(allyloxycarbonyl)glycine methyl ester in 40 mL of THF is added dropwise to a solution of 0.02 mol of 4isocyanatoacetophenone and 5 mL of pyridine in 40 mL of THF, and the reaction mixture is stirred for 3 hours. The solvent is then removed by rotary evaporator. The residue is dispersed in 50 mL of CH3OH, and 0.022 mol of hydroxylamine hydrochloride and 0.06 mol of trimethyl orthoformate are added. The reaction mixture is heated to reflux for 1 hour. The solvent is removed by rotary evaporator to give the product, N-[4-(1-hydroxyiminoethyl)phenyl]-N'-allyloxycarbonyl-N'methoxycarbonylmethylurea.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([NH:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24](=[O:26])[NH:25][C:21]=2[CH:20]=1)=[O:17]>C(OCC)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]([NH:18][C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24](=[O:26])[NH:25][C:21]=3[CH:20]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)[nH]c2c1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2[nH]c(=O)[nH]c2c1

Procedure:
The title compound is prepared from 4-benzyl-piperidine and 2-chloro-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-acetamide according to the method described in Example 142b. Melting Point: 270° C. (diethylether
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O-:30])=[O:29].Br[C:32]1[C:33]([O:40][CH3:41])=[N:34][C:35]([CH3:39])=[CH:36][C:37]=1[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCO[CH2:50][CH2:49]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([C:32]2[C:33]([O:40][CH3:41])=[N:34][C:35]([CH3:39])=[CH:36][C:37]=2[CH3:38])[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:49][CH3:50])=[O:29]
Reactant: CC1(C)OB(c2cc(F)c(-c3c(C(=O)[O-])cnn3[C@H]3CCOC3)cc2F)OC1(C)C
Reactant: C1COCCO1
Reactant: COc1nc(C)cc(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(-c2c(C)cc(C)nc2OC)cc1F
Temperature: 25 °C

Procedure:
Ethyl 5-(4-bromo-2,5-difluorophenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (4.31 g), bis(pinacolato)diboron (3.27 g), potassium acetate (3.16 g), Pd(dppf)Cl2-DCM complex (439 mg) were added to DMF (41.6 mL), and the reaction mixture was stirred at 95° C. in a nitrogen atmosphere. After stirring the reaction mixture for about 2 hours, the reaction mixture was stirred at 105° C. for about 4 hours. The reaction mixture was cooled to room temperature and then filtered through Celite™. The filtrate was concentrated under reduced pressure, and after brine and ethyl acetate were added to the residue the solution was stirred at room temperature for 5 minutes. The reaction mixture was again filtered through Celite™, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtrated through Celite™. The filtrate was concentrated, and the residue was purified by silica gel chromatography (heptane/ethyl acetate, 20% to 30% to 80%) to give ethyl 5-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (2.95 g). Eethyl 5-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (812 mg), 3-bromo-2-methoxy-4,6-dimethylpyridine (490 mg), Pd(PPh3)4 (130 mg) and cesium carbonate (1.77 g) were added to a mixed solvent of 1,4-dioxane (9.00 mL) and water (3.00 mL), and the reaction mixture was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature and partitioned by adding ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 11% to 30% to 50%) to give the title compound (397 mg). The title compound was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:31])([F:30])[C:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:16][C:13]1([C:12]([F:11])([F:30])[F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 3-(1-trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine. LCMS (MH+): m/z=451.1, tR (minutes, Method G)=2.58
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.Cl.[NH2:14][OH:15]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[N:14][OH:15])[CH2:8][CH2:7]1
Reactant: NO
Reactant: COCCCN1CCC(=O)CC1
Agent: Cl
Product: COCCCN1CCC(=NO)CC1

Procedure:
1-(3-Methoxypropyl)-4-piperidone oxime is prepared from 1-(3-methoxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][OH:9])[CH:2]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCCCBr
Reactant: OCCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCc1cccnc1
Reaction time: 3 h
Yield: 64.5 %

Procedure:
A mixture of 3-pyridineethanol (4 g), 1,6-dibromohexane (23.78 g), TAB (0.5 g) and 2N sodium hydroxide (50 ml) was vigorously stirred for 3 h. The mixture was diluted with water (75 ml), extracted with ethyl acetate and the combined organic extracts were washed with brine (150 ml), dried and evaporated. The resulting oil was purified by FCC eluting with hexane→hexane-ethyl acetate (19:1) to give 3-[2-[(6-bromohexyl)oxy]ethyl]pyridine (6 g). A solution of this bromocompound (5 g) and benzylamine (15 ml) was stirred at 140° under nitrogen for 1 h. The cooled reaction mixture was partitioned between sodium bicarbonate (150 ml) and ethyl acetate (50 ml). The organic layer was washed with brine (50 ml), dried and concentrated to give a yellow oil. The excess benzylamine was removed by distillation and the resulting oil was purified by FCC eluting with System C (95:5:1) to give the title compound as a yellow oil (4 g), t.l.c. (System A 80:20:1) Rf 0.5.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])=[CH:17][CH3:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:16]=[CH:17][CH3:18]
Reactant: CC=Cc1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CC=Cc1ccccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 7 h
Yield: 43 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-(1-propenyl)phenol (231 μl), and 4-dimethylaminopyridine (220 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for 7 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Thereafter, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (137 mg, yield 43%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.C(N(C(C)C)C(C)C)C.[C:21](=O)(OC(Cl)(Cl)Cl)[O:22]C(Cl)(Cl)Cl.[NH2:33][C:34]1[CH:61]=[CH:60][C:37]([C:38]([N:40]2[CH2:45][CH2:44][N:43]([CH2:46][C:47]3[CH:48]=[C:49]([CH:57]=[CH:58][CH:59]=3)[C:50]([NH:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:42][CH2:41]2)=[O:39])=[CH:36][C:35]=1[F:62]>ClCCl>[C:53]([NH:52][C:50](=[O:51])[C:49]1[CH:57]=[CH:58][CH:59]=[C:47]([CH2:46][N:43]2[CH2:44][CH2:45][N:40]([C:38](=[O:39])[C:37]3[CH:60]=[CH:61][C:34]([NH:33][C:21]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]=4)=[O:22])=[C:35]([F:62])[CH:36]=3)[CH2:41][CH2:42]2)[CH:48]=1)([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccc(C(F)(F)F)cn4)c(F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
5-(Trifluoromethyl)pyridin-2-amine (0.485 mmol, 0.079 g) and N-ethyl-N-isopropylpropan-2-amine (0.727 mmol, 0.120 mL, 0.094 g) were added to a stirred solution of bis(trichloromethyl) carbonate (0.160 mmol, 0.047 g) in dichloromethane (10 mL). The reaction was stirred for 3 hours at room temperature. 3-((4-(4-Amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.242 mmol, 0.1 g) was added and the reaction stirred for 30 minutes. The reaction was heated in the microwave at 120° C. for 10 minutes. The reaction was concentrated under vacuum and purified by acidic reverse phase HPLC to afford the title compound (50 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:4]=2[N:3]=1.N1CCOCC1.Cl.C(OCC)C>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)CCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Yield: 56.1 %

Procedure:
A solution of 8-chloro-3-(3-methylbutyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.074 g, 0.25 mmol) in THF (2 ml) was treated with morpholine (0.035 ml, 4.0 mmol) and the mixture degassed by the repeated alternate application of vacuum and nitrogen to the reaction vessel. The mixture was then treated with a solution of tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol) in degassed THF (0.5 ml). After 2 hours the mixture was treated with 2M aqueous hydrochloric acid (2 ml) and diethyl ether (3 ml). The precipitated product was filtered off, washed with diethyl ether and dried. This yielded the title compound as a white solid (0.036 g, 56%). NMR δH (400 MHz, d6-DMSO); 0.91 (d, 6H, J=6.3 Hz), 1.47-1.62 (m, 3H), 3.87 (t, 2H, J=7.5 Hz), 11.19 (br. s, 1H), 14.38 (br. s, 1H); m/z 257, 259[MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:17])=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:5])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.C(C(=NOC(N(C)C)=[N+](C)C)C(OCC)=O)#N.[CH2:47]([NH2:51])[CH2:48][CH2:49][CH3:50]>CN(C)C=O>[CH2:47]([NH:51][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[CH:7]=[C:6]([CH3:17])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12])[CH2:48][CH2:49][CH3:50]
Reactant: CCCCN
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNC(=O)c1ccccc1C=C(C)C(=O)OCC
Yield: 78.1 %

Procedure:
Ethyl 3-(2-butylcarbamoylphenyl)-2-methylacrylate is prepared as described in Example 30, starting with 1.17 g (5.0 mmol) of 2-(2-ethoxycarbonylpropen-1-yl)benzoic acid in 10 cm3 of dimethylformamide, a solution of 0.69 cm3 (5.0 mmol) of triethylamine, 1.64 g (5.0 mmol) of O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) in 6 cm3 of dimethylformamide and a second solution consisting of 366 mg (5.0 mmol) of n-butylamine and 0.69 cm3 (5.0 mmol) of triethylamine in 10 cm3 of dimethylformamide. 1.13 g of ethyl 3-(2-butylcarbamoylphenyl)-2-methylacrylate are thus obtained in the form of a yellowish oil, which can be reacted in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH:15][CH:16]=[O:17])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[Ca+2].[C:26](Cl)(Cl)=[S:27]>O1CCOCC1.O>[CH:16]([NH:15][NH:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5]([C:4]2[CH:3]=[C:2]([N:1]=[C:26]=[S:27])[CH:20]=[CH:19][CH:18]=2)=[O:6])=[CH:13][CH:12]=1)=[O:17]
Reactant: Nc1cccc(C(=O)Nc2ccc(NNC=O)cc2)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: O=CNNc1ccc(NC(=O)c2cccc(N=C=S)c2)cc1
Yield: 71.3 %

Procedure:
51 g of 2-[4-(3-aminobenzamido)phenyl]-1-formylhydrazine and 29 g of calcium carbonate were dispersed in a mixture of 120 ml of dioxane and 120 ml of water. To the dispersion, 25 g of thiophosgene was added under cooling with ice. After reacting under cooling with ice for 3 hours, the crystals deposited were collected by filtration to obtain 42 g of the object compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:15])=O.[C:18]([O:21]C(=O)C)(=O)[CH3:19]>C(O)(=O)C.CN(C=O)C>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([Cl:15])(=[O:10])=[O:11])=[CH:6][CH:7]=1)(=[O:21])[CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Yield: 83 %

Procedure:
6.285 g (36.08 mmol) of 4-hydroxybenzenesulfonic acid was dissolved in a mixture of 30 mL of acetic anhydride and 15 mL of acetic acid and refluxed for 6 hours. The volatiles were evaporated and placed under high vacuum overnight. The resulting crude product was dissolved in 100 mL of DCM and treated with 4.72 mL of oxalyl chloride (54.12 mmol) and 139 μL of DMF (1.804 mmol) at 0° C. Stirring was continued until gas evolution ceased then the reaction was concentrated and re-dissolved in EtOAc. The organic layer was washed twice with 2 N H2SO4, and dried with brine and MgSO4. concentration gave 7.067 g of 4-(chlorosulfonyl)phenyl acetate as a dark thick oil that eventually solidified (83% yield over two steps).
Reaction SMILES: [H-].[Na+].C([CH:5]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:6]([OH:8])=[O:7])C.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:26](OCC)(=O)[CH3:27].CCCCCC>CN(C)C=O>[CH2:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:5][C:6]([O:8][CH2:26][CH3:27])=[O:7])=[CH:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC(C(=O)O)c1c[nH]c2ccccc12
Reactant: CCOC(C)=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Combine sodium hydride (1.08 g, 60% in oil, 27.1 mmol) and dimethylformamide (50 mL). Add a solution of ethyl indol-3-yl-acetic acid (5 g, 24.6 mmol) in dimethylformamide (20 mL). Stir until gas evolution ceases. Add benzyl bromide (5.85 mL, 49.2 mmol). Warm to ambient temperature. After 48 hours, partition the reaction mixture between ethyl acetate and water. Separate the organic layer and extract with a saturated sodium chloride solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)O)=[O:4].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:31])=[C:28]([NH2:30])[CH:29]=1.C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.NC1C(=O)N(C)C=C(Cl)C=1>>[Br:10][C:8]1[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]([CH:14]([NH:30][C:28]2[CH:29]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=2[CH3:31])[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cn1
Reactant: Cc1ccc(Cl)cc1N
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cn1cc(Cl)cc(N)c1=O
Product: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1cc(Cl)ccc1C)c1ccc(Cl)cn1

Procedure:
The title compound was prepared in analogy to the procedure described for Step L3 but 5-bromo-2-[(5-chloro-pyridin-2-yl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step BK2) and 5-chloro-2-methyl-phenylamine were used instead of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-amino-5-chloro-1-methyl-1H-pyridin-2-one respectively. The title compound was obtained as a yellow-brown solid. ESI-MS: tR=1.59 min, [M+H]+ 510/512/514 (LC-MS 1).