Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C@H:6]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:12]3[CH2:13][C@@H:14]3[O:19][C@@:18]4([O:25][CH2:24][C@H:22]([CH3:23])[CH2:21][CH2:20]4)[C@@H:16]([CH3:17])[C@@H:15]32)[CH2:7]1)[CH3:2].C[OH:36].[OH-].[Na+].OO>O1CCCC1>[CH2:1]([O:3][CH2:4][O:5][C@H:6]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:8]([C@@H:9]([OH:36])[CH2:10][C@@H:11]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:12]3[CH2:13][C@@H:14]3[O:19][C@@:18]4([O:25][CH2:24][C@H:22]([CH3:23])[CH2:21][CH2:20]4)[C@@H:16]([CH3:17])[C@@H:15]32)[CH2:7]1)[CH3:2]
Reactant: CCOCO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4C[C@@H]5O[C@]6(CC[C@@H](C)CO6)[C@@H](C)[C@@H]5[C@@]4(C)CC[C@@H]32)C1
Reactant: CO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOCO[C@H]1CC[C@@]2(C)[C@H](C1)[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3[C@H](C[C@@H]12)O[C@]1(CC[C@@H](C)CO1)[C@H]3C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Borane-tetrahydrofurancomplex (0.68 mL, 0.68 mmol) was added to a solution of (3β,25R)-3-ethoxymethoxy-5-spirostene (0.10 g, 0.21 mmol) in tetrahydrofuran (8 mL). The mixture was stirred under nitrogen atmosphere at ambient temperature for 3.5 hours. The reaction mixture was cooled to 0° C. and methanol (1.5 mL), 15% sodium hydroxide solution (1.5 mL) and 30% hydrogen peroxide (1.5 mL) were added. The reaction mixture was then gradually warmed to ambient temperature and stirred overnight. The reaction was quenched at 0° C. by the addition of saturated sodium bisulfite solution. The mixture was diluted with ethyl acetate and washed with ammonium chloride solution (1x), brine (1x), dried (sodium sulfate), filtered and concentrated in vacuo to give 0.11 g of a mixture of the 6α-alcohol and the 6β-alcohol. The two products were separated by flash chromatography on silica gel (6:4 hexane/ethyl acetate). The major product (Rf=0.40) was identified to be the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:12]([N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:28][C:16]=2[C:15]1=[O:35])[CH3:13]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:14]([CH2:12][CH3:13])[C:15](=[O:35])[C:16]2[CH:28]=[N:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][C:17]1=2)=[O:4]
Reactant: CCN1C(=O)c2cnc(-c3ccccc3)nc2Nc2ccccc21
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1C(=O)c2cnc(-c3ccccc3)nc2N(C(=O)CCl)c2ccccc21
Temperature: 100 °C
Reaction time: 20 h

Procedure:
28 g (250 mmol) of chloroacetyl chloride and 28 g (250 mmol) of sodium carbonate are added to a solution of 20 g (63 mmol) of 6-ethyl-2-phenyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 500 ml of absolute toluene. The mixture is stirred for 20 hours at 100° C. The solvent is removed on a rotary evaporator, and the residue is neutralized with 2 N-hydrochloric acid. The mixture is extracted with chloroform, and the organic phase is washed with water, dried and concentrated in vacuo. The residue which remains is recrystallized from isopropanol; yield: 19.2 g (77%), m.p. 147° to 148° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](Cl)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[N:7][CH:6]=3)[N:4]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3ccnnc3)no2)cc1F

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3,4-difluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.80 (dt, J=10.5, 8.3 Hz, 1H), 8.08-8.19 (m, 1H), 8.29 (dd, J=5.4, 2.4 Hz, 1H), 8.31-8.38 (m, 1H), 9.55 (dd, J=5.4, 1.4 Hz, 1H), 9.82 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z 261 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][S:44]([OH:46])=[O:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][S:44]([OH:46])=[O:45])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Reactant: NCCCS(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCS(=O)O)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added compound (25) (100 mmol), 3-aminopropylsulfinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the title compound (39) as a white solid.
Reaction SMILES: C(OC([N:7]1[C@H:11]([CH2:12][C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[CH:15][N:14]=2)[CH2:10][C@H:9]([S:21][C:22]2[C@H:23]([CH3:39])[C@@H:24]3[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:25]3[C:26]=2[C:27]([O:29]CC=C)=[O:28])[CH2:8]1)=O)C=C.CNC1C=CC=CC=1.O>ClCCl.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>[OH:37][C@@H:35]([C@H:34]1[C:33](=[O:38])[N:25]2[C:26]([C:27]([OH:29])=[O:28])=[C:22]([S:21][C@H:9]3[CH2:10][C@@H:11]([CH2:12][C:13]4[N:20]5[C:16]([S:17][CH:18]=[CH:19]5)=[CH:15][N:14]=4)[NH:7][CH2:8]3)[C@H:23]([CH3:39])[C@H:24]12)[CH3:36]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CNc1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](Cc4ncc5sccn45)C3)[C@H](C)[C@H]12
Yield: 61.8 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (7.0 mg) is added to a solution of 34.5 mg of allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-5-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate and 0.040 ml of N-methylaniline in 1.2 ml of dry dichloromethane in an argon atmosphere at room temperature for 60 min. Distilled water (3 ml) is added thereto, the mixture is washed three times with 6 ml of ethyl acetate, and the aqueous layer is filtered, followed by concentration under reduced pressure and freeze drying to give 16.7 mg of a colorless flocculent material. The colorless flocculent material is purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 9.8 mg of the title compound as a colorless flocculent material.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH3:12])=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:17][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:15])([F:14])[F:1])=[CH:5][CH:6]=1)[CH2:11][CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CCC(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Br)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1-(4-(trifluoromethoxy)phenyl)propan-1-ol (300 mg; 1.36 mmol) in anh. DCM (10 ml) was treated at rt with CBr4 (451 mg; 1.36 mmol), and with PPh3 (357 mg; 1.36 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 1-(1-bromopropyl)-4-(trifluoromethoxy)benzene as a slightly yellow oil which was directly used for the next reaction. LC-MS (conditions A): tR=1.01 min.; no ionisation.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.[N:13]#[C:14]Br.C(=O)([O-])[O-].[Na+].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl.O>[OH:12][CH:9]1[CH2:10][CH2:11][N:6]([C:14]#[N:13])[CH2:7][CH2:8]1
Reactant: OC1CCNCC1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: N#CN1CCC(O)CC1
Yield: 82 %

Procedure:
To sodium bicarbonate (8.31 g, 99 mmol) was gradually added water (5 mL) with vigorous stirring to a uniform slurry. The flask was placed in an ice bath, and a solution of piperidin-4-ol (5 g, 49.4 mmol) in CH2Cl2 (12.5 mL) was added and the contents were vigorously mixed while cooling. To the above mixture was added a solution of cyanic bromide (6.28 g, 59.3 mmol) in CH2Cl2 (5 mL) dropwise over 15 min. After completion, the mixture was stirred for at 0° C. for 1 h, then at rt overnight. To the reaction mixture was added sodium carbonate (1.048 g, 9.89 mmol) to ensure complete neutralization. MgSO4 was added and the mixture was stirred vigorously for 15 min. The resulting suspension was filtered, rinsed with CH2Cl2. The filtrated was concentrated to afford 4-hydroxypiperidine-1-carbonitrile (5.11 g, 40.5 mmol, 82% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.61-1.73 (m, 3H) 1.95 (dddd, J=13.07, 7.01, 3.41, 3.28 Hz, 2H) 3.04-3.15 (m, 2H) 3.42-3.51 (m, 2H) 3.89 (tq, 1H).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][N:13]([CH3:27])[S:14]([C:17]1[C:18]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].[Cl:28][C:29]1[N:34]=[C:33]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[C:32](=[O:45])[N:31]([CH3:46])[CH:30]=1.C(O)(=O)C>C(#N)C>[Cl:28][C:29]1[N:34]=[C:33]([NH:35][C:36]([NH:26][S:23]([C:18]2[C:17]([S:14]([N:13]([CH3:27])[CH3:12])(=[O:16])=[O:15])=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:24])=[O:37])[C:32](=[O:45])[N:31]([CH3:46])[CH:30]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1S(N)(=O)=O
Reactant: Cn1cc(Cl)nc(NC(=O)Oc2ccccc2)c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cn(C)c1=O
Reaction time: 3 h
Yield: 84.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.30 mL, 2.00 mmol) was added dropwise over two minutes to a mixture of N,N-dimethyl-1,2-benzenedisulfonamide (0.53 g, 2.00 mmol) and phenyl (6-chloro-3,4-dihydro-4-methyl-3-oxopyrazin-2-yl)carbamate (0.56 g, 2.00 mmol) in anhydrous acetonitrile (20 mL) under nitrogen. After 3 hours at room temperature, glacial acetic acid (0.12 mL, 2.10 mmol) was added. The solvent was rotary evaporated and the residue was chromatographed on a column of silica gel using a solvent mixture of 1:1 dichloromethane-ether containing 2 mL/L acetic acid as eluant. The appropriate fractions were evaporated to leave 0.76 g of N'-[(6-chloro-3,4-dihydro-4-methyl-3-oxopyrazin-2-yl)aminocarbonyl]-N,N-dimethyl-1,2-benzenedisulfonamide as a crystalline solid melting at 227°-230° C.
Reaction SMILES: ClC1C=C(F)C(C2N=NN(C)N=2)=C(C2C=C(F)C([C@H](NC(=O)C)C)=NC=2)C=1.BrC1C=C(Cl)C=C(F)C=1C1N=NN(C)N=1.ClC1C=C(F)C(C2N=NN(C)N=2)=C(C2C=C(F)C([C@H](N)C)=NC=2)C=1.C1C2C(COC(=O)[NH:83][C:84]3([C:88](=[O:113])[NH:89][C@@H:90]([C:92]4[C:97]([F:98])=[CH:96][C:95]([C:99]5[CH:104]=[C:103]([Cl:105])[CH:102]=[C:101]([F:106])[C:100]=5[C:107]5[N:108]=[N:109][N:110]([CH3:112])[N:111]=5)=[CH:94][N:93]=4)[CH3:91])[CH2:87][O:86][CH2:85]3)C3C(=CC=CC=3)C=2C=CC=1>>[Cl:105][C:103]1[CH:102]=[C:101]([F:106])[C:100]([C:107]2[N:108]=[N:109][N:110]([CH3:112])[N:111]=2)=[C:99]([C:95]2[CH:96]=[C:97]([F:98])[C:92]([C@H:90]([NH:89][C:88]([C:84]3([NH2:83])[CH2:87][O:86][CH2:85]3)=[O:113])[CH3:91])=[N:93][CH:94]=2)[CH:104]=1
Reactant: C[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)COC1)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Agent: CC(=O)N[C@H](C)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Agent: C[C@@H](N)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Agent: Cn1nnc(-c2c(F)cc(Cl)cc2Br)n1
Product: C[C@@H](NC(=O)C1(N)COC1)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F

Procedure:
The title compound was prepared in analogy to intermediate 1 synthesizing N—((R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-acetamide in step A (using 5-(2-bromo-4-chloro-6-fluoro-phenyl)-2-methyl-2H-tetrazole (intermediate 11) instead of 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole), (R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylamine in step B and [3-((R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-carbamic acid 9H-fluoren-9-ylmethyl ester in step C. White solid. MS: 450.2 [M+H]+.
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])=[C:26]1[CH3:37]>>[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])[C:26]=2[CH3:37])=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
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)c2c(C)n(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 1,2-Dimethyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.93 min; [M+H]+=519.3.
Reaction SMILES: BrCC(Br)=O.[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:17])[CH2:15][CH3:16])[C:8]=1[NH2:9].[Br:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Br:18][CH2:19][CH2:20][C:21]([NH:9][C:8]1[C:10]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:11][CH:12]=[CH:13][C:7]=1[CH3:6])=[O:22]
Reactant: CCC(=O)c1cccc(C)c1N
Reactant: O=C(Cl)CCBr
Agent: O=C(Br)CBr
Product: CCC(=O)c1cccc(C)c1NC(=O)CCBr

Procedure:
In the same manner as in Example 1 but replacing 2-acetyl-6-methylaniline and bromacetyl bromide by 2-methyl-6-propionylaniline and 3-bromopropionyl chloride, there was obtained 3-bromo-2'-methyl-6'-propionylpropionanilide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[Br:16]Br.O>CCCCCC>[Br:16][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: c1ccc2c(c1)CCO2
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Brc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,3-dihydrobenzofuran (11.06 g) and sodium carbonate (14.8 g) in hexane (100 ml) was added dropwise at 0° C. a solution of bromine (4.8 ml) in hexane (20 ml) for 1.5 hours, and the mixture was stirred at room temperature for 1 hour. To the mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give gray crystals of 5-bromo-2,3-dihydrobenzofuran (17.64 g).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:22]1([O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:30][C@H:29]([C:28]([O:27][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:5][CH:4]=1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: O=Cc1ccc(CBr)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)C[C@H](NCc1ccc(CBr)cc1)C(=O)OC1CCCC1
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 4-(bromomethyl)-benzaldehyde (0.940 g, 4.72 mmol) in dichloroethane (20 mL) was added L-leucine cyclopentyl ester tosylate (2.40 g, 6.4 mmol) and sodium triacetoxyborohydride (2.53 g, 11.9 mmol). The reaction mixture was stirred for 1 hour then poured into ethyl acetate (300 mL). The organic fraction was washed with saturated sodium hydrogen carbonate (100 mL, 3 times 50 mL) then dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, gradient 0-3% methanol-dichloromethane) to yield the desired product (1.504 g, 83% yield). LC/MS: m/z 382/384 [M+H]+
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28].[K+].[Br-]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=2)(=[O:29])=[O:28])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Oc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(CCc3c(Cc4ccccc4)sc4ccccc34)cc2)cc1O

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[2-(2-benzyl-benzo[b]thiophen-3-yl)-ethyl]-phenol (0.400 g, 1.16 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.550 g, 2.32 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with 20% EtOAc/hexane gave the tide compound as an off white solid, mp 57-59° C. 1H NMR (DMSO-d6) δ2.74 (t, 2H), 3.09 (t, 2H), 4.00 (s, 2H), 6.97 (d, 2H), 7.19-7.23 (m, 5H), 7.27-7.38 (m, 6H), 7.76 (d, 1H), 7.83 (dd, 1H), 7.98 (d, 1H). IR (KBr) 3400, 2950, 1675, 1390 and 1190 cm−1. mass spectrum (−ESI) m/z 543 (M−H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:31][C:32]1[CH:41]=[C:40]2[C:35]([CH:36]=[CH:37][CH:38]=[C:39]2[O:42][CH2:43][CH2:44][O:45][CH3:46])=[CH:34][CH:33]=1>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH:15]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]2[C:40](=[C:39]([O:42][CH2:43][CH2:44][O:45][CH3:46])[CH:38]=[CH:37][CH:36]=2)[CH:41]=1)[CH:16]([CH3:17])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOc1cccc2ccc(CBr)cc12
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOc1cccc2ccc(CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)C(C)C)cc12
Reaction time: 0.5 h

Procedure:
A solution of 0.31 g of 4(R)-benzyl-3-(3-methylbutyryl)oxazolidin-2-one in 2 ml of tetrahydrofuran is added dropwise at −78° C. to 1.2 ml of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofuran). After 30 minutes, a solution of 0.30 g of 7-bromomethyl-1-(2-methoxyethoxy)naphthalene in 2 ml of tetrahydrofuran is added dropwise and the reaction mixture is allowed to thaw from −78° C. to 0° C. over 2 hours. After 3 hours at 0° C., the reaction mixture is quenched with 5 ml of 1M ammonium chloride solution, diluted with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:39](Cl)(=[O:41])=[O:40])[CH2:36][CH2:37][CH3:38]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:39]([CH2:35][CH2:36][CH2:37][CH3:38])(=[O:41])=[O:40])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CCCCS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 1-butanesulfonyl chloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[Cl:36])[CH3:27]>CN(C=O)C.[Cu]I>[Cl:36][C:29]1[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=1/[C:26](/[CH3:27])=[CH:25]\[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1cc(F)c(F)cc1Cl
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2-chloro-4,5-difluorobenzene (321 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. Yield: 10 mg as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.30 (m, 1H), 7.18 (s, 1H), 7.10 (m, 2H), 6.95 (d, 1H), 6.90 (s, 1H), 4.40 (d, 1H), 4.22 (d, 1H), 3.80 (m, 1H), 3.45 (m, 1H), 3.10 (m, 2H), 3.0 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]([NH2:9])(=[O:8])[CH3:7]>C(O)(=O)C>[C:6]([NH:9][CH:2]([OH:3])[C:1]([OH:5])=[O:4])(=[O:8])[CH3:7]
Reactant: O=CC(=O)O
Reactant: CC(N)=O
Solvent: CC(=O)O
Product: CC(=O)NC(O)C(=O)O

Procedure:
An acetic acid solution of acetamidoglycolic acid is prepared by distilling under vacuum without exceeding 40° C the water from a mixture of 74 g of aqueous solution of 50% glyoxylic acid (0.5 mole) and 29.55 g of acetamide (0.5 mole).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[C:4](I)[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[CH:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[C:4]([C:20]#[C:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])[CH:3]=1
Reactant: COc1cc(Cl)cc(I)c1N
Reactant: C#Cc1ccccc1Cl
Product: COc1cc(Cl)cc(C#Cc2ccccc2Cl)c1N

Procedure:
The title compound was prepared in analogy to example 10 step A from 4-chloro-2-iodo-6-methoxy-phenylamine (300 mg, 1.06 mmol) and 1-chloro-2-ethynyl-benzene (174 mg, 1.27 mmol). Brown solid (220 mg, 71%). LC-MS (ESI): 292 (M+H)+.