Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[C:16]1(B(O)O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][C:18]2[CH:17]=[CH:16][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: OB(O)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc3ccccc3c2)cc(C(=O)OC)c1
Yield: 76 %

Procedure:
A solution of 5-hydroxyisophthalic acid dimethylester (208 mg, 1 mmol) and 2 naphthaleneboronic acid (172 mg, 1 mmol), Cu (OAc)2 (61 mg, 0.5 mmol), Et3N (0.16 ml, 1.2 mmol) in 10 ml methylenechloride was refluxed for overnight. The reaction mixture was purified by silica gel column eluted by 15% Teac in hexane to afford the product (76% yield).
Reaction SMILES: [I-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=O)[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-:19].[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:2]([NH:9][C:10](=[O:19])[C:11]1[CH2:12][CH:13]=[CH:14][NH:17][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccc[n+](Cc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: O=C(NCc1ccccc1)C1=CNC=CC1
Yield: 72.5 %

Procedure:
To a solution of 1-benzylpyridinium-3-carboxamide iodide (1 g, 3.41 mmol) in H2O (15 mL) was added sodium carbonate (1.44 g, 13.64 mmol) and sodium dithionite (2.65 g, 12.96 mmol) at room temperature. The resulting solution was stirred under nitrogen in darkness for 15 mn. The reaction mixture was then extracted with dichloromethane. The combined organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure at room temperature to afford N-benzyl-1,4-dihydronicotinamide (BNAH) (0.530 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31]>CN(C=O)C.C(N(CC)CC)C.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]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: C#CC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reaction time: 16 h

Procedure:
To a solution of compounds 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (500 mg, 1.09 mmol) and 3,3-Dimethyl-but-1-yne (385 mg, 4.69 mmol) in DMF (0.5 mL), triethylamine (1.06 mL) and tris(dibenzylideneacetone)dipalladium (0) (70 mg, 0.08 mmol) are added and the reaction mixture is stirred under reflux conditions for 16 h under a N2 atmosphere. DMF and triethylamine are removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic layer is separated, dried (Na2SO4), concentrated and the residue is purified by column chromatography using ethyl acetate and hexane (1:2) as eluent to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a solid, 330 mg (66%).
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc3c(O)ncnc3o2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(-c2cc3c(Cl)ncnc3o2)c1
Temperature: 0 °C

Procedure:
11 g of 4-hydroxy-6-(3-nitrophenyl)furo[2,3-d]pyrimidine are heated for 4 h to RF in ca. 340 ml of phosphorus oxychloride. Afterwards, the reaction mixture is left to stand over night and then added to 5 kg of drained ice. The resulting suspension is filtered by suction and washed with a lot of H2O. The residue is dried in a HV and sublimated at ca. 200° C.; m.p.: 196-205° C.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]1)=[CH:10][C:9]2=[O:21])[CH3:3].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>CC(N(C)C)=O>[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][CH:2]([C:4]2[CH:5]=[C:6]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]2)=[CH:10][C:9]3=[O:21])[CH3:3])=[CH:30][CH:29]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@@H](C)C3)oc12
Reactant: Nc1ccc(F)cc1
Solvent: CC(=O)N(C)C
Product: CC(Nc1ccc(F)cc1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@@H](C)C3)oc12
Yield: 51 %

Procedure:
8-(1-bromoethyl)-N,N-dimethyl-2-((S)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (110 mg, 0.20 mmol) and 4-fluoroaniline in DMA (1 mL) were stirred at 50° C. for 5 hrs. The reaction mixture was purified by preparative HPLC on a Waters X-Bridge system. The fractions containing the desired compound were concentrated. The obtained gum was triturated in diethyl ether and petroleum ether, the resulting solid was collected by filtration and dried to afford 8-(1-(4-fluorophenylamino)ethyl)-N,N-dimethyl-2-((S)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (45 mg, 51%) as a white solid. Mass Spectrum: M+H+ 545. NMR Spectrum (CDCl3): 1.25 (d, 1.5H), 1.26 (d, 1.5H), 1.61 (d, 3H), 2.77-2.88 (m, 1H), 2.83 (bs, 3H), 3.06 (bs, 3H), 3.13-3.22 (m, 1H), 3.64-3.82 (m, 4H), 3.97 (bs, 1H), 3.98-4.06 (m, 1H), 4.91 (q, 1H), 5.56 (s, 1H), 6.37-6.43 (m, 2H), 6.82 (t, 2H), 7.73 (d, 1H), 8.11 (d, 1H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([N:28]6[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]6)=[CH:35][CH:36]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound, white solid (99 mg, 77%), MS (ISP) m/z=518.5 [(M+H)+], mp 182.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-piperidin-1-yl-benzoic acid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=2[F:31])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C)cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Reactant: Fc1ccc(CBr)c(F)c1
Product: C=CCOc1cc(C)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 89C and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9](O)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=S)C.C(N(CC)CC)C.C[S:25](Cl)(=O)=O.C[O-].[Na+]>ClCCl.CO>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C@@H:9]2[CH2:8][CH2:7][CH2:6][CH2:5][S:25]2)[CH:11]=1
Reactant: CC(=S)OCCCC[C@@H](O)c1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: c1cncc([C@@H]2CCCCS2)c1
Temperature: 25 °C

Procedure:
A solution of (R)-5-hydroxy-5-(3-pyridyl)pentyl thioacetate (10.0 g) in dichloromethane (200 ml) under nitrogen is cooled to 0° C. and treated with triethylamine (7 ml), followed by methanesulphonyl chloride (3.8 ml), dropwise between -5° C. and 0° C., during 5 minutes. The reaction mixture is then warmed to room temperature. After 60 minutes the mixture is cooled to 10° C. and treated, dropwise during 10 minutes, with a solution of sodium methoxide in methanol (20 ml; 25% w/v). The mixture is allowed to warm to room temperature. After 30 minutes the mixture is washed with water until the pH is between 9 and 10, dried over magnesium sulphate, evaporated and chromatographed, to give (S)-2-(3-pyridyl)tetrahydro-2H-thiopyran (7.5 g; 91% ee), in the form of an amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:20]=C([CH:24]=[CH:25][CH:26]=3)C#N)[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-:34].[Na+].Cl.[CH3:37][CH2:38][OH:39]>>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:20]=[C:37]([CH:24]=[CH:25][CH:26]=3)[C:38]([OH:34])=[O:39])[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCO
Reactant: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C(=O)O)c2)C1

Procedure:
A mixture of 5.52 g (10.4 mmol) of 3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]benzonitrile, 65 mL of EtOH, and 40 mL of 5N NaOH was heated to reflux for 4 h (with monitoring by HPLC). Then the pH solution was adjusted to 4-5 with 12N HCl and the solution was concentrated to remove organic solvents. The residue was dissolved in 200 mL of CH2Cl2 and filtered to remove undissolved solid. The solid residue was triturated with two 200 mL portions of CH2Cl2 and the combined organic layers were concentrated to the title compound as white solid; Mass Spectrum: m/e=548, (M+1, 35Cl 79Br), 550 (M+1, 37Cl79Br/35Cl 81Br), 552 (M+1, 37Cl 81Br).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.Cl.[N:24]1([C:29](N)=[NH:30])C=CC=N1.C(N(CC)C(C)C)C.O>CN(C=O)C>[NH:1]([CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2)[C:29]([NH2:30])=[NH:24]
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reactant: N=C(N)n1cccn1
Agent: CCN(CC)C(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Temperature: 100 °C

Procedure:
N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide, 1H-pyrazol-1-carboxamidine hydrochloride and diethyl isopropylamine are dissolved in DMF, and the reaction mixture is heated to 100° C., then cooled and diluted by addition of of water. The aqueous mixture is extracted with EtOAc, and the combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure to give N-(5-Guanidinomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide. 5-Guanidinomethyl-5,6,7,8-tetrahydro-naphthalene-2-sulfonic acid phenylamide may be similarly prepared.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.O.[CH2:23](O)[CH3:24]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:23][CH3:24])=[O:17])=[CH:11][CH:10]=2)=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of 27.3 g of [p-(p-nitrophenoxy)phenyl]acetic acid in 270 ml of ethanol is cooled to 0° C and saturated with dry HCl gas over 3 1/2 hours. The resulting deep red solution is heated to reflux and maintained at reflux overnight. A yellow crystalline solid separates on cooling. The entire mixture is poured into 500 ml of water and extracted with three 200 ml portions of benzene. The combined extracts are washed with two 150 ml portions of water, two 150 ml portions of saturated NaHCO3, 150 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords an oil which yields yellow crystals from 50 ml of ethanol, mp 70.5°-73° C. Recrystallization from ethanol affords yellow prisms, mp 70.5°-73° C.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:5][CH:4]=1.Cl.C(OCC)(=O)C>C1COCC1.CO>[C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
1N Aqueous sodium hydroxide solution (8 ml) was added to a mixed solution of methyl 4-(4-biphenylylcarbonylamino)benzoate (1.998 g) in THF (60 ml) and methanol (20 ml), which was stirred at room temperature for 18 hours. 1N Hydrochloric acid (10 ml) was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The resulting crude crystals were washed with diethyl ether to give the titled compound (1.760 g).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.Br.BrCC1C=CC=CN=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]2)[C:21]1=[O:40].FC1C2OCCOC=2C=C2OCC3(C4C(=CC=CC=4)NC3=O)C=12>>[O:40]=[C:21]1[C:22]2([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]2)[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]1[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Agent: Br
Agent: BrCc1ccccn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Product: O=C1N(Cc2cc(=O)[nH]c(=O)[nH]2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 5.25 and making non-critical variations using 6-(chloromethyl)uracil to replace 2-(bromomethyl)pyridine hydrobromide, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 6-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]pyrdimidine-2,4(1H,3H)-dione was obtained (5%) as an off-white solid: mp>300° C.; 1H NMR (300 MHz, DMSO-d6) δ11.11 (s, 1H), 11.05 (s, 1H), 7.29 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=6.8 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 7.03 (dd, J=7.7, 7.7 Hz, 1H), 6.66 (s, 1H), 6.26 (s, 1H), 5.90 (s, 2H), 5.14 (s, 1H), 4.75 (ABq, 2H), 4.60 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.4, 164.2, 155.9, 151.8, 151.5, 148.8, 142.3, 142.2, 132.1, 129.4, 124.2, 123.9, 120.1, 109.8, 103.6, 101.9, 96.9, 93.8, 80.4, 57.9, 40.5; MS (ES+) m/z 406.3 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[CH:26]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cn(C)c3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1-Methyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.91 min; [M+H]+=505.4.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](C)[C:6]=1[C:7]([O:9]CC)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH2:38][CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:32]1([CH2:38][CH2:39][N:40]2[C:7](=[O:9])[C:6]3[CH:5]=[CH:4][S:3][C:2]=3[NH:1][C:17]2=[O:23])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: NCCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2sccc2c(=O)n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution (150 mL) of ethyl 2-amino-4-methylthiophene-3-carboxylate (3 g) in methylene chloride were added triphosgene (2.45 g) and triethylamine (4.21 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-phenylethanamine (7.2 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (100 mL), sodium methoxide (9.2 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (5.2 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][C:9]=2[CH3:11])[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:3]1.[H-].[Na+].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31].[OH-].[Na+]>C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][S:30]([C:24]3[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])(=[O:32])=[O:31])=[CH:8][C:9]=2[CH3:11])[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:3]1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Cc1cc(O)cc2c(C3CCN(C)CC3)cn(C)c12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OS(=O)(=O)c2c(F)cccc2F)cc2c(C3CCN(C)CC3)cn(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A suspension of 1,7-dimethyl-3-(1-methylpiperdin-4-yl)-5-hydroxy-1H-indole (1.0 eq, 1.98 mmol, 0.511 g) in THF (5.0 mL) at room temperature was added 60% sodium hydride (1.2 eq, 2.37 mmol, 0.095 g). After stirring five minutes 2,6-difluorobenzenesulfonyl chloride (1.1 eq, 2.18 mmol, 0.384 g) was added. The reactions were stirred at room temperature for 3 hours. The reaction was treated with water (25 mL) and 1N sodium hydroxide (2 mL) then extracted with ethyl acetate (2×25 mL). The organic phases were combined, washed with water (25 mL) then brine (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to an oil. This material was subjected to radial chromatography, 4 mm plate, eluting with 9:1 chloroform:2M ammonia in methanol. Fractions containing product were combined, concentrated in vacuo to afford an oil. The title compound was crystallized from diethyl ether to afford 0.592 g (59%) of the title compound: mp=139° C.; Mass spectrum (ion spray): m/z=439 (M+1); 1H NMR (DMSOd6): 7.95-7.85 (m, 1H), 7.43-7.37 (m, 2H), 7.05 (s, 1H), 6.84 (d, J=2.20 Hz, 1H), 6.64 (d, J=1.46 Hz, 1H), 3.96 (s, 3H), 2.79 (m, 2H), 2.64 (s, 3H), 2.50-2.40 (m, 1H), 2.19 (s, 3H), 1.96 (m, 1H), 1.92 (m, 1H), 1.69-1.56 (m, 2H), 1.53 (m, 1H), 1.44 (m, 1H); Calculated for C22H26N2F2O3S: C, 60.89; H, 5.57; N, 6.45. Found: C, 60.67; H, 5.64; N, 6.54.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC1(C)C(C)(C)OB([C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH:22]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.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>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH:22]=2)[CH:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(I)c1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
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: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(C2=CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
To a solution of 3-iodo-4-nitroanisole (4.21 g, 15.1 mmol) in 1,2-dimethoxyethane (50 mL) were added 4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane (4.78 g, 18.1 mmol) produced in Example (4b), tripotassium phosphate (4.81 g, 22.7 mmol) and water (3 mL). Then, tetrakis(triphenylphosphine)palladium(0) (870 mg, 0.755 mmol) was added to the mixture while stirring at room temperature under a nitrogen atmosphere. The mixture was then further stirred for 13 hours at an external temperature of 70° C. To the reaction mixture were added tetrakis(triphenylphosphine)palladium(0) (870 mg, 0.755 mmol) and water (3 mL), followed by stirring for 26 hours at an external temperature of 100° C. The reaction mixture was cooled, and then ethyl acetate was added and the mixture was filtered through Celite. The filtrate was concentrated to give a residue, which was subjected to extraction with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 1.5 g of the title compound as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[O:15][CH2:14]2.[H][H]>[Pd].CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[O:15][CH2:14]2
Reactant: O=C1OCc2cc(C#CCOC3CCCCO3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1OCc2cc(CCCOC3CCCCO3)ccc21
Yield: 98.6 %

Procedure:
A mixture of 5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-3H-isobenzofuran-1-one (1.0 g, 3.67 mmol) and 10% palladium on carbon (200 mg) in MeOH (15 ml) was shaken under 45 psi of hydrogen for 20 hours. The catalyst was removed by filtration through celite and rinsed with MeOH. The combined filtrates were evaporated to give 5-[3-(tetrahydro-pyran-2-yloxy)-propyl]-3H-isobenzofuran-1-one as a light yellow oil (1.0 g, 99%).