Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-].[Na+].[C:4](OC)(=O)[CH2:5][C:6](C)=[O:7].[CH3:12][O:13][CH:14]([O:20][CH3:21])[C:15](C)=[CH:16][CH2:17]Cl.[OH-].[Na+]>CO>[CH3:21][O:20][C:14]([O:13][CH3:12])([CH3:1])[CH2:15][CH2:16][CH:17]=[C:5]([CH3:4])[CH:6]=[O:7]
Reactant: COC(=O)CC(C)=O
Reactant: C[O-]
Reactant: COC(OC)C(C)=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(C)(CCC=C(C)C=O)OC
Reaction time: 2 h

Procedure:
180 g (1 mole) of 30% solution of sodium methylate in methanol is added over 15 minutes at 150° to 20°C to 116 g (1 mole) of methyl acetoacetate. The whole is stirred for another hour at 20° to 30° C and then 156 g (0.95 mole) of 2-methyl-4-chloro-2-buten-1-al dimethylacetal is added to the solution at 20°C over 30 minutes. The reaction mixture obtained is stirred for 15 hours at room temperature, then 400 g of 10% caustic soda solution is added and stirring is continued for another 2 hours at 60°C. The salt-like constituents are separated by filtration and the organic products are isolated by extraction with ether. Before the ethereal solution is distilled it is washed with saturated common salt solution. The ether is then distilled off and the residue is fractionated. The boiling point is 72° to 83° C at 0.9 to 1.5 mm and the refractive index nD25 = 1.4474.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH2:7][CH2:6][NH:5][C:4]1=[S:8].[C:11](Cl)([Cl:13])=[O:12]>C(Cl)Cl>[Cl:13][C:11]([N:3]1[CH2:7][CH2:6][NH:5][C:4]1=[S:8])=[O:12]
Reactant: O=C(Cl)Cl
Reactant: C[Si](C)(C)N1CCNC1=S
Solvent: ClCCl
Product: O=C(Cl)N1CCNC1=S
Temperature: 0 °C
Reaction time: 24 h

Procedure:
50 parts by weight of 1-trimethylsilyl-imidazolidine-2-thione in 150 parts by volume of methylene chloride were treated with 35 parts by weight of phosgene in 50 parts by volume of methylene chloride over the course of 2 hours at 0° C. The mixture was stirred for 24 hours at 0° C, the methylene chloride was subsequently stripped off, and the residue was dried in a high vacuum. Semi-solid mass, incompletely soluble in aceteone. Crude yield: 97% IR bands at 1830, 1590 and 1240 cm-1.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH3:9])=[CH:3][CH:2]=1.O.[OH-].[Li+].O1CCCC1.CO>O>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([O:7][CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)[CH3:9])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccc(C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(OC(C)c2ccc(C(=O)O)cc2)cc1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 4-(1-(p-tolyloxy)ethyl)benzoate (50 mg, 0.19 mmol), lithium hydroxide monohydrate (39 mg, 0.92 mmol), tetrahydrofuran (6 mL), methanol (2 mL), and water (2 mL) were stirred at 20° C. for 12 hours. The reaction mixture was concentrated, acidified with concentrated hydrochloric acid to pH=1, extracted with ethyl acetate (20 mL×3). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give 4-(1-(p-tolyloxy)ethyl)benzoic acid used in next step without further purification (42 mg, 86%). LRMS (M+H)− m/z: calcd 256.11. found 256.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][S:30]([CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:32])=[O:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:38]2[CH2:37][CH2:36][N:35]([CH2:34][CH2:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH2:40][CH2:39]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CCS(C)(=O)=O)CC3)n(C)c2n1
Reaction time: 64 h

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (60 mg, 0.16 mmol), 1-(2-methanesulfonylethyl)piperazine (37 mg, 0.19 mmol) and 4 Å powdered molecular sieves (100 mg) in DCE (4 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (67 mg, 0.32 mmol). The reaction mixture was stirred for 64 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 329 as a cream solid (55 mg, 62%). LCMS (Method G): RT 5.54 min [M+H]+ 554.3. 1H NMR (CDCl3, 400 MHz): δ 8.11-8.06 (m, 1 H); 7.74-7.70 (m, 1 H); 7.30-7.25 (m, 2 H); 4.35 (m, 4 H); 3.90-3.82 (m, 7H); 3.76 (s, 2 H); 3.15 (t, J=6.4 Hz, 2 H); 3.04 (s, 3 H); 2.95 (s, 3 H); 2.90 (t, J=6.4 Hz, 2 H) and 2.57 (m, 8 H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].ClC1C=CC(C(NC2C=CC=C(C3OCCO3)C=2)=O)=CC=1.N1CCC(C(OC)=O)C1.C([O:43][C:44]([CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([NH:59]C(=O)C3C=CC(Cl)=CC=3)[CH:54]=2)[CH2:48]C1)=[O:45])C>>[CH3:1][C:2]1[CH:10]=[C:6]([C:7]([NH:59][C:55]2[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=2)[CH2:52][N:49]2[CH2:50][CH2:51][CH:46]([C:44]([OH:43])=[O:45])[CH2:48]2)=[O:8])[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Reactant: Cc1cncc(C(=O)Cl)c1
Agent: COC(=O)C1CCNC1
Agent: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Product: Cc1cncc(C(=O)Nc2cccc(CN3CCC(C(=O)O)C3)c2)c1

Procedure:
The title compound is prepared according to the reaction sequence 2.001a-2.001d described above using 5-methylnicotinoyl chloride instead of 4-chlorobenzoyl chloride as in 2.001a and methyl pyrrolidine-3-carboxylate instead of ethyl isonipecotate as in 2.001c: LC-MS A: tR=0. 45 min; [M+H]+=340.14.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:24](P(=O)(OCC)OCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(C)=O.CC(C)([O-])C.[K+]>O>[Br:1][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1c2ccccc2c(-c2ccc(C=Cc3ccccc3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 85.6 %

Procedure:
Under an atmosphere of argon, 9-bromo-10-(4-formylphenyl)anthracene (3.9 g, 11 mmole) and diethyl benzylphosphonate (3 g, 13 mmole, 1.2 eq) were suspended into DMSO (25 ml). To the resultant suspension, potassium t-butoxide (1.6 g, 14 mmole, 1.1 eq) was added and the obtained mixture was stirred at the room temperature for 10 hours and left standing for one night. The reaction mixture was diluted with water (50 ml) and subjected to extraction with toluene (300 ml). The organic layer was washed with water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml) and dried with magnesium sulfate. Then, the solvent was removed by distillation and a yellow solid was obtained. The obtained solid was purified by recrystallization from toluene (40 ml) and yellow needle crystals (4.1 g, 86%) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=[N:17][OH:18])[N:13]=[C:12]([CH3:19])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:34][CH2:35][C@@H:36]2[CH2:41][O:40][C@@H:39]([CH:42]=[CH2:43])[CH2:38][O:37]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:34][CH2:35][C@@H:36]2[CH2:41][O:40][C@@H:39]([C@H:42]3[O:18][N:17]=[C:16]([C:14]4[CH:15]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]5[CH:20]=[CH:21][C:2]([F:1])=[C:3]([O:22][CH3:23])[CH:4]=5)[N:11]=[C:12]([CH3:19])[N:13]=4)[CH2:43]3)[CH2:38][O:37]2)(=[O:32])=[O:33])=[CH:27][CH:26]=1
Reactant: C=C[C@H]1CO[C@H](COS(=O)(=O)c2ccc(C)cc2)CO1
Reactant: COc1cc(CNC(=O)c2cc(C=NO)nc(C)n2)ccc1F
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](COS(=O)(=O)c5ccc(C)cc5)CO4)C3)nc(C)n2)ccc1F
Reaction time: 5 h
Yield: 24.3 %

Procedure:
To a stirred solution of N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methyl pyrimidine-4-carboxamide (3.84 g, 12.08 mmol, Preparation #9) and ((2S,5S)-5-vinyl-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (3.0 g, 10.06 mmol, Preparation#11) in CHC3 (30 mL), was added iodobenzene diacetate (6.48 g, 20.13 mmol, Aldrich) portion wise (divided in to 4 equal portions and added over a period of 4 hrs). After the addition is completed, the reaction mixture was stirred for another 5 h and quenched with water (100 mL). The product was extracted with DCM (2×100 mL). Combined organic layers were washed with brine solution (100 mL), dried over sodiumsulphate and evaporated to dryness. The residue obtained containing two diastereomers and other impurities was purified by flash column chromatography using silica gel (230-400 mesh) eluting with 40% EtOAc in n-hexane. First eluting compound fractions were combined and evaporated to dryness under reduced pressure, triturated with 40% EtOAc in hexane to afford ((2S,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate 1.5 g (24%). 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 8.28 (t, J=6.4 Hz, 1H), 7.79 (d, J=8 Hz, 2H), 7.36 (d, J=8 Hz, 2H), 7.08-6.96 (m, 2H), 6.90-6.86 (m, 1H), 4.68-4.60 (m, 3H), 4.02-3.93 (m, 2H), 3.88 (s, 3H), 3.85-3.72 (m, 5H), 3.59-3.38 (m, 5H), 2.75 (s, 3H), 2.42 (s, 3H); MS m/z: 615 (m+H)+.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][CH2:2][CH2:3][C:4]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: Nc1ccccc1Cl
Reactant: COC(=O)C1(CC=O)CCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1(CCNc2ccccc2Cl)CCCN1C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
A solution of 1-tert-butyl 2-methyl 2-(2-oxoethyl)pyrrolidine-1,2-dicarboxylate (220 mg, 0.00081 mol) in DCM (anhydrous, 4 mL) was added to 2-chloroaniline (110 μL, 0.0010 mol) and the resulting solution was stirred for 20 min. Sodium triacetoxyborohydride (290 mg, 0.0014 mol) was then added to the mixture. After stirring at RT for 12 h, the reaction mixture was diluted with EtOAc and quenched by the addition of water. The crude mixture was filtered through a pad of diatomaceous earth and the filter pad were washed several times with EtOAc and the resulting layers were of the filtrate separated. The aqueous phase was extracted with EtOAc (3×10 mL) and the combined organic phases were washed with brine (2×5 mL). The organic phase was then dried (NaSO4), filtered, and concentrated in vacuo to afford the desired product. LC-MS: 327.1 (M−Boc+2H)+ and 383.2 (M+1H)+.
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:28]=[CH:27][C:23](C([O-])=O)=[CH:22][CH:21]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-:29].[Na+].[O:31]1[CH2:35]C[CH2:33][CH2:32]1>C(O)C>[N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:33][C:32]([O:31][CH3:35])=[O:29])=[CH:27][CH:28]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Agent: [Na+]
Solvent: CCO
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Using General Procedure I; a solution of ethyl [4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate (Compound 138, 50.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (87%) of the title compound as a colorless solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH3:21])/[C:16]([O:18]CC)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]>C(O)C.O1CCCC1>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2OCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)O)cc2OCCCC)c1
Temperature: 50 °C
Yield: 62.3 %

Procedure:
40 mg (1 mmol) of sodium hydroxide are added to a solution of 526 mg (1.1 mmol) of ethyl (E)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methylacrylate in 1 mL of ethanol and 10 mL of tetrahydrofuran. The reaction mixture is heated at 50° C. for 24 hours. The reaction medium is evaporated to dryness, taken up in water and acidified with aqueous 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the oil obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture and then precipitated from heptane. 310 mg (91%) of (E)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methylacrylic acid are obtained in the form of a white solid with a melting point of 87-89° C.
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[CH:25]1([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[CH:25]1([C:30]2[CH:37]=[CH:36][C:33]([CH2:34][NH:48][CH2:47][CH2:46][C:41]3[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=3)=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=Cc1ccc(C2CCCC2)cc1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ccc(CCNCc2ccc(C3CCCC3)cc2)cc1Cl

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 160 mg of 4-cyclopentyl-benzaldehyde (0.92 mmol), 175 mg of 2-(3,4-dichloro-phenyl)-ethylamine (0.92 mmol) and 52 mg of sodium borohydride (1.38 mmol). The isolated light yellow oil (183 mg, 57%) was used in the following step without further purification. MS (ISP) 348.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([C:8]1[C:16]([F:17])=[CH:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=1)=[O:7].C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.B.O>O1CCCC1.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([C:8]1[C:16]([F:17])=[CH:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=1)[OH:7]
Reactant: O=C(COCCCl)c1cc2ccsc2cc1F
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OC(COCCCl)c1cc2ccsc2cc1F
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To a solution of 4.5 g of 2-(2-chloroethoxy)-1-(6-fluorobenzo[b]thiophen-5-yl)ethanone in 45 ml of tetrahydrofuran is added 0.46 g of (R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine at -10° C., and thereafter, 9.9 ml of 1 M borane solution of tetrahydrofuran is dropwise added thereto. The temperature of the resulting mixture is elevated to room temperature, and the mixture is stirred at the same temperature for 1.5 hours, after which 100 ml of water and 100 ml of ethyl acetate are added thereto. The resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is then removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent:toluene:ethyl acetate=10:1], to obtain 4.5 g of oily (+)-2-(2-chloroethoxy)-1-(6-fluoro-benzo[b]thiophen-5-yl)ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:62]3[CH2:63][CH2:64][N:59]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[CH3:52])[CH2:60][CH2:61]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC2CO2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC(O)CN2CCN(c3ccccc3C)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A solution of 1-[3-(4-chloro-3-nitro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.754 g, 2.0 mmol) in dichloromethane (10 mL) was treated with ytterbium(III) triflate (0.25 g, 0.40 mmol) and 1-(2-methylphenyl)-piperazine (0.705 g, 4.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and diluted with dichloromethane (100 mL) and water (50 mL). The organic layer was separated, washed with water (2×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% MeOH/CH2Cl2) to afford 0.98 g (90%) of the desired product as a light yellow solid. MS (electrospray): m/z 553.2 (553.2, calculated for C28H33ClN6O4, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 8.25-8.15 (m, 1H), 7.75-7.70 (m, 1H), 7.63-7.55 (m, 1H) 7.20-7.10(m, 2H), 7.05-6.95 (m, 2H), 4.90-4.70 (m, 1H), 4.65 (s, 1H), 4.30-4.15 (m, 2H), 4.10-3.70 (m, 4H), 3.00-2.40 (m, 12H), 2.20(s, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C[Si]([O:20][S:21](Cl)(=[O:23])=[O:22])(C)C.CO>ClC(Cl)C>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:21]([OH:23])(=[O:22])=[O:20])=[CH:8]1
Reactant: c1ccc2c(c1)ccn2CC1=NCCN1
Reactant: C[Si](C)(C)OS(=O)(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CO
Product: O=S(=O)(O)c1cn(CC2=NCCN2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-1H-indole (1.0 g, 4.243 mmol) was dissolved/suspended in dichloroethane (120 ml) and cooled in ice under a nitrogen atmosphere. Trimethylsilylchlorosulfonate (0.654 ml, 0.801 g, 4.243 mmol) was added to the cooled solution dropwise with stirring. The mixture was allowed to warm up to room temperature with stirring, and stirring was continued overnight. Methanol (20 mL) was then added, followed by stirring at room temperature for 20 minutes. The mixture was then rotovapped to dryness. The crude product was recrystallized from MeOH/EtOAc as the hydrochloride salt of 1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:15][C:16]#[CH:17].C1COCC1>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:17][C:16]#[CH:15])(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C#CCBr
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: C#CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Yield: 86.4 %

Procedure:
199 g (1.0 mol) of 4-acetylaminobenzenesulfinic acid were dissolved in 1000 ml of water at pH 6, the solution was added dropwise to a solution of 140 g (1.1 mol) of 3-bromoprop-1-yne and 200 ml of THF at from 40° to 50° C., and the mixture was maintained at that temperature until the reaction had ended (check by TLC). The precipitate formed was filtered off with suction at about 10° C., washed neutral with water and dried, leaving 205 g of 4-acetylamino-1-(prop-1-yn-3-ylsulfonyl)benzene (melting point 175°-179° C.). ##STR26##
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=O)=[CH:4][C:3]=1[CH3:15].C1COCC1.[OH-].[Na+]>CO>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(C(=O)N2CCOCC2)sc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CN2CCOCC2)sc1Br
Temperature: 25 °C

Procedure:
(5-Bromo-4-methyl-thiophen-2-yl)-morpholin-4-yl-methanone (1.78 mmol) was added to a flask containing 1M THF.BH3 complex in THF (4.45 mmol). Reaction was stirred at reflux for 2.5 h under N2. Methanol was then added until gas evolution ceased, followed by 10 ml of 1M NaOH and the reaction stirred at reflux for a further 7 h. The mixture was cooled to room temperature and extracted with EtOAc. This extract was concentrated in vacuo and the residue taken up in 1M HCl and washed with EtOAc. The acid layer was then basified with 1M NaOH and extracted back into EtOAc. Removal of solvent gave 4-(5-Bromo-4-methyl-thiophen-2-ylmethyl)-morpholine as a colourless oil: m/z in MS ES+=276, 278 [M+H]+, 0.98 mmol, 55%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.[C:13](=O)([O-])[O-].[K+].[K+].[CH2:19]([OH:21])[CH3:20]>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][CH2:20][C:19](=[O:21])[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CCO
Reactant: ClCCCc1ccccc1CCl
Agent: [K+]
Product: CC(=O)CCc1ccccc1CCCCl

Procedure:
A mixture of 258 g (1.27 mol) of 2-(3-chloropropyl)benzyl chloride, 2, 140 g (1.4 mol) of 2,4-pantanedione, 6, 175 g (1.27 mol) potassium carbonate, and 700 ml of absolute ethanol was stirred at reflux for 18 hours. Evaporation of the alchohol gave a residue which was partitioned between ether and water. The organic phase was dried over anhydrus MgSO4, concentrated and the residue distilled to give the chloro ketone 7, 218 g, bp 123°-127° C/0.2 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrC1CCCC1
Reactant: Nc1ccc(OCc2ccc3ccccc3n2)cc1
Product: c1ccc2nc(COc3ccc(NC4CCCC4)cc3)ccc2c1

Procedure:
The title compound was prepared at a temperature of +40°-+50° C. from 10 g (0.04 mol) of the compound from Example 1 and 6 g (0.04 mol) of cyclopentyl bromide in analogy to Example 13.