Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20].CN([CH:26]=[O:27])C>CCOCC.O>[O:1]([C:8]1[CH:12]=[C:11]([CH:26]=[O:27])[S:10][C:9]=1[Si:19]([CH3:21])([CH3:20])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccsc2)cc1
Reactant: C[Si](C)(C)Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)c1sc(C=O)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a 0° C. solution of 3-phenoxythiophene (9.5 g, 53.9 mMol) in ether (200 mL) was added n-butyllithium (24 mL, 60 mMol, 2.5M in hexanes). The reaction was stirred for 15 min and trimethylsilyl chloride (6.45 g, 59.4 mMol) was added via syringe. The reaction was stirred 15 min and additional n-butyllithium (24 mL, 60 mMol, 2.5M in hexanes) was added and the reaction stirred 15 min. To the cold reaction mixture is added DMF (14 mL) and the reaction allowed to warm to room temperature over night. Water (5 mL) was added cautiously while stirring. The reaction mixture was diluted with ether and washed with water. The aqueous layer was washed with ether and the organic layer combined, washed with brine, dried (MgSO4), and concentrated. Purification by flash chromatography (SiO2, eluted with 5% ether/hexanes) afforded 4-phenoxy-5-trimethylsilylthiophene-2-carboxaldehyde (12.1 g, 83%) as a slightly yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:14]([OH:15])[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:16][CH3:17])[CH2:12][S:11](=[O:23])(=[O:22])[C:10]3[CH:24]=[CH:25][C:26]([N:28]([CH3:30])[CH3:29])=[CH:27][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:31](O)(=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C1(N=C=NC2CCCCC2)CCCCC1.N1(O)C2C=CC=CC=2N=N1>O1CCCC1>[CH2:18]([C:13]1([CH2:16][CH3:17])[CH2:12][S:11](=[O:22])(=[O:23])[C:10]2[CH:24]=[CH:25][C:26]([N:28]([CH3:29])[CH3:30])=[CH:27][C:9]=2[CH:8]([C:4]2[CH:3]=[C:2]([NH:1][C:31]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:39])[CH:7]=[CH:6][CH:5]=2)[CH:14]1[OH:15])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(N)c2)C1O
Reactant: O=C(O)CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)CCCCC(=O)O)c2)C1O

Procedure:
2 g of 5-(3-aminophenyl)-3-butyl-7-dimethylamino-3-ethyl-1,1-dioxo-2,3,4,5-tetra-hydro-1H-benzo[b]thiepin-4-ol, 3.4 g of hexanedioic acid, 1.04 g of dicyclohexylcarbodiimide and 640 mg of benzotriazol-1-ol in 80 ml of tetrahydrofuran are stirred at room temperature overnight. The mixture is concentrated, the residue is taken up in ethyl acetate, excess urea is removed by filtration and the mixture is washed with water. The residue of the dried organic phase is purified by column filtration (SiO2, dichloromethane/methanol=20:1). This gives the product of molecular weight 558.7 (C30H42N2O6S); MS (ESI+): 559 (M+H+).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:18]=2)[NH:13][C:12]1=[O:30])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:31]([O:33][C:34]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)=[O:35])[CH3:32].O>CN(C=O)C>[CH2:31]([O:33][C:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:4](=[C:11]2\[C:12](=[O:30])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:42][CH:43]=1)=[O:35])[CH3:32]
Reactant: CCOC(=C1C(=O)Nc2ccc(NS(=O)(=O)c3ccccc3)cc21)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
0.84 g (2 mmol) of 3-(1-ethoxy-1-phenyl-methylidene)-5-phenylsulphonylamino-2-indolinone and 0.39 g (2.2 mmol) of 4-ethoxycarbonylmethyl-aniline are dissolved in 10 ml of DMF. The mixture is heated to 140° C. for 5 hours. Then water is added while the mixture is cooled with ice and stirred for 1 hour at ambient temperature. The precipitate formed is suction filtered, washed with water, a little isopropanol and ether, then dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[C:13]([N:20]1[CH2:25][CH2:24][N:23]2[CH2:26][C@H:27]([CH2:30]OS(C)(=O)=O)[CH2:28][CH2:29][C@H:22]2[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl>CN(C=O)C.O>[C:13]([N:20]1[CH2:25][CH2:24][N:23]2[CH2:26][C@H:27]([CH2:30][N:7]3[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[CH2:28][CH2:29][C@H:22]2[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](COS(C)(=O)=O)CC[C@H]2C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C[C@H](Cn3ccc4cc(F)ccc43)CC[C@H]2C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
A solution of 8.41 g (62 mmol) of 5-fluoroindole in 250 mL of DMF was treated with 2.46 g (62 mmol) of sodium hydride (60% oil dispersion) and the mixture stirred at 50° C. for 1.5 h. Heating was stopped temporarily, 7.73 g (22.2 mmol) of (7R,9aS)-2-BOC-7-(methanesulfonyloxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 250 mL of DMF was added, and the mixture stirred at 100° C. for 2 h. The mixture was cooled to room temperature, diluted with water, acidified to pH 2 with 6M hydrochloric acid, and washed with ethyl acetate. The aqueous phase was basified to pH 12 with conc. ammonium hydroxide and extracted with ethyl acetate (3×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 3.09 g (36%) of (7R,9aS)-2-BOC-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1(C)[CH2:10][CH:9]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[C:6]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].[CH3:25][Si](C)(C)[N-][Si](C)(C)C.[K+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br>C1COCC1>[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40][N:2]([CH3:1])[C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CNC(=O)C1(C)CC=C(N2CCN(C)CC2)C=C1c1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ccc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 29 %

Procedure:
To a solution of 50 mg (0.15 mmol)2-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid methylamide in 2 ml THF 0.2 ml of a 1 M solution (0.2 mmol) of potassium hexamethyldisilazide in THF was added at 0°. After 20 min. 0.028 ml (0.15 mmol) 3,5-bis(trifluoromethyl)benzyl bromide was added dropwise to the resulting suspension. The reaction was quenched with water after 1.5 h. The mixture was diluted with 5 ml 2 N NaOH solution and extracted with 3 5-ml portions of ethyl acetate. The combined organic extracts were dried (Na2SO4) and evaporated. Chromatography (SiO2, CH2Cl2/methanol 19:1) gave 25 mg (29%) 2′-Methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, MS (ISP): 550.5(M+H)+.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1.Cl.[Br:30]N1C(=O)CCC1=O>CO>[Br:30][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:13]2[C:12]3[CH:25]=[C:26]([O:27][CH3:28])[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CNCC2
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: COc1cc2c(cc1OC)C(Oc1ccc(Br)cc1)CNCC2
Temperature: 25 °C
Yield: 28.8 %

Procedure:
A solution of 7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine of Example 35 (6.5 g, 22 mmole) in 300 ml methanol was acidified to pH 1 with ethereal hydrogen chloride. After this solution was cooled with an ice bath, N-bromosuccinimide (4.2 g, 24 mmole) was added. The reaction mixture slowly warmed to ambient temperature, was evaporated, stirred with water, basified with saturated sodium carbonate and was extracted with ethyl acetate-ether. The organic extracts were washed with water, saturated sodium chloride and were dried (anhydrous MgSO4), filtered and evaporated to 8 g of an oil. This oil was converted to the maleate salt (8 g, 74%, m.p. 95°-100° C.) by the addition of ethereal maleic acid of which 4 g was recrystallized twice from isopropanol-ether to give 2.4 g (45%) of 1-(4-bromophenoxy)-7,8-dimethoxy-2,3,4,5-tetrahydro-3-benzazepine meleate, d 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:17][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=1)[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)C(Br)Oc1ccc(Cl)cc1
Yield: 76 %

Procedure:
German Laid-Open Application DOS 2,720,654 discloses that alkanecarboxylic acid derivatives, for example tert.-butyl 4-chlorophenoxyacetate, can be reacted with N-bromosuccinimide in the presence of a solvent and of a source of free radicals, such as dibenzoyl peroxide or azo-bis-isobutyronitrile, to give tert.-butyl bromo-(4-chlorophenoxy)-acetate. In the case of tert.-butyl 4-chlorophenoxyacetate it is stated that a reaction time of 2 hours is required and a yield of 76 percent is obtained. If the process is carried out with the corresponding propionic acid esters, especially on an industrial scale, substantially longer reaction times, for example from 8 to 15 hours, are required to obtain yields of from 60 to 80% of theory.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([Cl:15])[C:6]([Cl:14])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:16].[CH:17]1[CH:22]=CC=C[CH:18]=1.C(=O)CC>[Zn].CS(C)=O>[Cl:14][C:6]1[C:5]([Cl:15])=[C:4]2[C:9]([CH2:10][CH2:11][C:2](=[CH:18][CH2:17][CH3:22])[C:3]2=[O:16])=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(Br)CC2
Reactant: c1ccccc1
Agent: [Zn]
Solvent: CS(C)=O
Solvent: CCC=O
Product: CCC=C1CCc2cc(OC)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
2-Bromo-7,8-dichloro-6-methoxy-1-tetralone (0.01 mole), benzene (50 ml), dimethyl sulfoxide (5 ml), propionaldehyde (3 ml, 0.04 mole) and zinc dust (6.5 g, 0.1 mole) were stirred under nitrogen. After 48 hours, the reaction mixture was poured into ice water, washed with brine, dried over MgSO4 and filtered, treated with 300 mg of para-toluene sulfonic acid, then refluxed for 15 minutes. The reaction mixture was cooled, filtered, evaporated and chromatographed on 140 g SiO2 (ethyl acetatehexane 3:7) to yield 1.25 g of 7,8-dichloro-6-methoxy-2-propylidene-1-tetralone which was directly used in Step C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=4)[CH:20]=3)[CH2:14][CH2:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=2)=[N:43][CH:44]=1>>[ClH:37].[ClH:37].[ClH:37].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=4)[CH:20]=3)[CH2:16][CH2:17]2)[CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]3[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=3)=[N:43][CH:44]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Product: COc1cc(OC)cc(N(Cc2ccc(-c3cc(OC)c(OC)c(OC)c3)nc2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)c1
Product: Cl

Procedure:
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[CH2:19]=O.Cl>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH:11]([CH3:19])[CH2:12][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: C=O
Reactant: CCC(=O)c1ccc(C(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(CN1CCCC1)C(=O)c1ccc(C(C)C)cc1

Procedure:
To a solution of 10.00 g of 4'-isopropylpropiophenone in 80 ml of ethyl acetate were added 2.00 g of pyrrolidine and 2.50 g of paraformaldehyde. The mixture was acidified by the addition of gaseous hydrogen chloride and refluxed for 4 hours.
Reaction SMILES: [NH2:1][C:2]1[C:7](C(O)=O)=[C:6]([CH3:11])[N:5]=[C:4]2[S:12][C:13]([Br:16])=[C:14]([CH3:15])[C:3]=12.C1(OC2C=CC=CC=2)C=CC=CC=1>CO>[Br:16][C:13]1[S:12][C:4]2[N:5]=[C:6]([CH3:11])[CH:7]=[C:2]([NH2:1])[C:3]=2[C:14]=1[CH3:15]
Reactant: Cc1nc2sc(Br)c(C)c2c(N)c1C(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Product: Cc1cc(N)c2c(C)c(Br)sc2n1
Temperature: 200 °C
Yield: 56.9 %

Procedure:
A mixture of 4-amino-2-bromo-3,6-dimethylthieno[2,3-b]pyridine-5-carboxylic acid (Description 61) (720 mg, 2.391 mmol) and diphenyl ether (3.80 mL, 23.91 mmol) was heated to 200° C. for 48 h. The mixture was then cooled to RT, taken-up in MeOH (10 mL) and purified on silica, eluting with a gradient of 0-20% 2M NH3 in MeOH in DCM. Further purification by SCX, eluting with 0-100% 2M NH3 in MeOH in MeOH afforded the title compound (350 mg). LCMS (A) m/z: 257/259 [M+1]+, Rt 1.10 min (basic).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=O)[C:7]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].C[Si](C)(C)O[Si](C)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[S:20])[C:7]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2cc(Cl)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: S=C1c2ccc(Cl)cc2CCc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 191.9 %

Procedure:
To a stirred solution of 2,8-dichloro-10,11-dihydro-dibenzo[a,d]cycloheptene-5-one (0.70 g, 2.53 mMol) in toluene (20 ml) were added phosphorus pentasulfide (1 eq, 561 mg) and hexamethyldisiloxane (1 eq, 0.54 ml). The mixture was heated 3 h at reflux and allowed to cool to room temperature. The mixture was filtered through a pad of silica gel (70 g) and washed through with 8:1 heptane/ethyl acetate. Evaporation of the solvent under reduced pressure afforded 2,8-dichloro-10,11-dihydro-dibenzo[a,d]cycloheptene-5-thione as a blue solid (710 mg, 95%) that was used without further purification.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:3]1.Cl.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1)#[N:20]>CC(O)=O.O1CCOCC1.Cl.O>[O:17]=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[N:7]1[CH:4]1[CH2:5][C:6]2[NH:27][C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][C:25]=3[C:2]=2[CH2:3]1
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)C3
Yield: 66.4 %

Procedure:
Mix (±)-2-(3-oxo-cyclopentyl)-isoindole-1,3-dione (12.7 g, 55.3 mmol) and 4-cyanophenylhydrazine-HCl (8.53 g, 50.3 mmol) in HOAc (200 mL) and 4N HCl dioxane (50 mL). Using mechanical stirring, heat the reaction to 90° C. for 18 h, then add additional 4N HCl dioxane (20 mL). Heat the reaction to 100° C. for 18 h. Dilute the reaction mixture with water (600 mL) and collect a black solid by vacuum filtration. Sonicate the solid with MeOH (200 mL), then collect and dry in a vacuum oven to give 10.94 g (66%) of a gray-brown solid. MS (m/z): 328 (M+1), 326 (M−1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:11]=1[CH3:23].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[O:16]([C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[C:11]([CH2:23][Br:1])[CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(Oc2ccccc2)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Oc2ccccc2)ccc1Br

Procedure:
N-Bromosuccinimide (16.2 g) was added to a solution of 2-bromo-5-phenoxytoluene (15.3 g) in carbon tetrachloride (50 mls) containing benzoyl peroxide (0.05 g) and the mixture refluxed for ten hours. The precipitate of succinimide was filtered off and the filtrate washed with N-sodium hydroxide solution followed by water. Drying over magnesium sulphate and evaporation of the solvent gave, as a light yellow oil, 4-phenoxy-2-bromomethylphenyl bromide.
Reaction SMILES: [CH2:1]([O:8][C:9]1C=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=C[NH:38]C(=O)C=1)C1C=CC=CC=1.BrCC(C1C=CC(CO)=CC=1)=O>>[CH2:1]([O:8][C:9]1[N:38]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)nc[nH]1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Agent: O=C(CBr)c1ccc(CO)cc1
Product: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1

Procedure:
6-Benzyloxy-3-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-3H-pyrimidin-4-one is prepared following preparation 15b from 1.50 g (7.42 mmol) 6-benzyloxy-3H-pyrimidin-4-one and 1.87 g (8.16 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 15a).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl.O>CCCCCC.O1CCCC1>[Br:17][C:10]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=[CH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cccn1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)n1nccc1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a mixture of 17.6 g of N,N-dimethyl-1H-pyrazole-1-sulfonamide and 200 ml of tetrahydrofuran was added dropwise 80 ml of a 1.3M solution of n-butyl lithium in hexane at −78° C., and the resulting mixture was stirred at −78° C. for 15 minutes. To the mixture, a solution of 35.8 g of 1,2-dibromo-1,1,2,2-tetrachloroethane in 60 ml of tetrahydrofuran was added dropwise, and the resulting mixture was stirred at −78° C. for 15 minutes. The reaction mixture was returned to room temperature, and stirred for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 21.3 g of 5-bromo-N,N-dimethyl-1H-pyrazole-1-sulfonamide of the formula:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]2.[CH2:19](O)[CH3:20]>>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2
Reactant: CCO
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2cc(OC)ccc2[nH]1

Procedure:
1.91 ml (26.15 mmol) of thionyl chloride are added dropwise with stirring at 0° C. to a solution of 1 g (5.23 mmol) of 5-methoxy-1H-indole-2-carboxylic acid in 52 ml of ethanol. The reaction mixture is heated at reflux for 2 hours and then it is cooled and concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and this solution is washed with two times 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The solution is dried over magnesium sulfate and filtered, and then the filtrate is concentrated under reduced pressure. 1.2 g of product are obtained, which product is used as is in the following stage.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[S:9][C:8](=[O:11])[NH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[S:19]>CC(C)=O>[CH2:21]([O:20][P:18]([O:11][C:8]1[S:9][C:10]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[N:7]=1)([O:23][CH2:24][CH3:25])=[S:19])[CH3:22]
Reactant: CCOP(=S)(Cl)OCC
Reactant: O=C1CCCc2[nH]c(=O)sc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nc2c(s1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8.4 g of 7-oxo-2,3,4,5,6,7-hexahydrobenzothiazoline-2-one, 10.5 g of potassium carbonate and 100 ml of acetone was refluxed for 1 hour and after addition of 14.5 g of O,O-diethyl chlorothiophosphate thereto, the mixture was refluxed for another hour. The mixture was stirred at room temperature for 24 hours and the mineral salts formed were filtered off. The filtrate was distilled to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 6 -4 cyclohexane-ethyl acetate mixture resulted in 3.5 g of 2-(diethoxythiophosphoryloxy)-4,5,6,7-tetrahydro-7-oxo-benzothiazole with a refractive index of nD20 = 1.555.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:13])[N:4]([CH2:11][CH3:12])[C:5]([S:9][CH3:10])=[N:6][C:7]=1[OH:8].[CH:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:13])[N:4]([CH2:11][CH3:12])[C:5]([S:9][CH3:10])=[N:6][C:7]=1[O:8][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:21][CH:22]=1
Reactant: CCn1c(SC)nc(O)c(Br)c1=O
Reactant: ClCc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(SC)nc(OCc2ccc(C3CCCCC3)cc2)c(Br)c1=O
Yield: 100 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 1 g of 5-bromo-3-ethyl-6-hydroxy-2-methylthio-4(3H)-pyrimidinone and 0.8 g of 4-cyclohexylbenzyl chloride, and then 1 g of anhydrous potassium carbonate was added thereto. The mixture was subjected to a reaction at 80° C. for 3 hours. After allowing to cool in air, the resulting solution was poured into 50 ml of water and extracted twice with 30 ml of ethyl ether. The ethyl ether layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to give 1.65 g of a crude product.