Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:15]3[C:23]4[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[CH2:11][CH2:12][C:13]#[N:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1.CO>C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:15]3[C:23]4[C:18](=[C:19]([CH2:24][S:25]([CH3:26])=[O:38])[CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[CH2:11][CH2:12][C:13]#[N:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc4sccc4c3)c[nH]c12
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc4sccc4c3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
157 mg (0.42 mmol) of the compound from Example 52 were introduced into 28 ml of dichloromethane at 0° C., 102 mg (0.42 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol and a little ethyl acetate were added, and the mixture was extracted with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The phases were separated, and the solvents were removed from the organic phase in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) and afforded 141 mg (86% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:14](O)[CH3:15])[CH2:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:18][CH2:15][CH2:14][N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:10][CH2:11][O:12][CH3:13]
Reactant: COCCN(Cc1ccc(Cl)nc1)C(C)O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCN(CCBr)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (0° C.) solution of 1.25 grams (0.0051 mole) of 2-{[(6-chloro(3-pyridyl)methyl](2-methoxyethyl)amino}ethan-1-ol and 1.9 grams (0.0057 mole) of carbon tetrabromide in 70 mL of methylene chloride was added 1.66 grams (0.0064 mole) of triphenylphosphine. The reaction mixture was allowed to warm to ambient temperature where it stirred for 1.5 hours. After this time silica gel was added and the mixture concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel eluting with a 50/50 mixture of diethyl ether and hexanes. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.17 grams of (2-bromoethyl)[(6-chloro(3-pyridyl))methyl](2-methoxyethyl)amine as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:16]1[CH:17]=[C:18]([F:28])[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:14]([F:13])[CH:15]=1
Reactant: N#Cc1cc(Br)c2cn[nH]c2c1
Reactant: OB(O)c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(Br)c2cnn(-c3cc(F)c(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 4-bromo-1H-indazole-6-carbonitrile (1.0 g, 4.50 mmol) in dichloromethane (50 mL) was added {3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid {DE 4236105} (1.8 g, 6.82 mmol), pyridine (0.73 mL, 9.04 mmol), copper acetate (1.22 g, 6.74 mmol) and powdered 4A molecular sieves (5 g). The reaction mixture was stirred at room temperature in the presence of air for 6 days. Celite was added to the mixture and stirred for 5 mins then the mixture was filtered through a pad of celite and then the filtrate was washed with water, dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 10-100% ethyl acetate in hexane to yield the title compound (D36) (944 mg).
Reaction SMILES: ClC1C=CC2S[CH:7]=[C:8]([CH2:9][N:10]3[CH2:14][CH2:13][N:12]([C:15]4[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=4)[C:11]3=[O:24])[C:4]=2C=1.[CH:27]1([CH2:30][N:31]2[CH2:35][CH2:34][N:33](C3SC(C(O)=O)=C(C)N=3)C2=O)[CH2:29][CH2:28]1.N1C=CC=C(CN)C=1>>[CH:8]1([CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([NH:33][CH2:34][C:35]4[CH:29]=[CH:28][CH:27]=[CH:30][N:31]=4)=[O:23])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:24])[CH2:7][CH2:4]1
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ccccn1
Yield: 64 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 64% yield: mp 148-151° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.54 (d, J=4.9 Hz, 1H), 7.70-7.64 (m, 1H), 7.31-7.23 (m, 1H), 7.21-7.18 (m, 1H), 7.11-7.09 (m, 1H), 4.69 (d, J=4.9 Hz, 2H), 4.15-4.09 (m, 2H), 3.73-3.67 (m, 2H), 3.19 (d, J=7.1 Hz, 2H), 2.64 (s, 3H), 1.00-0.91 (m, 1H), 0.60-0.54 (m, 2H), 0.27-0.22 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.8, 155.9, 155.2, 152.4, 148.8, 136.8, 122.4, 122.0, 117.8, 48.6, 44.6, 42.3, 42.1, 17.2, 8.9, 3.4; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH2:32][C:33](=[O:37])[NH:34]2)=[CH:29][C:28]=1[F:38]>>[F:38][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:27]=1[NH:26][C:15]1[N:14]=[CH:13][C:12]3=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:17]3[N:16]=1)[NH:34][C:33](=[O:37])[CH2:32][CH2:31]2
Reactant: Nc1cc2c(cc1F)CCC(=O)N2
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Product: COc1ccc(-c2ccc3cnc(Nc4cc5c(cc4F)CCC(=O)N5)nn23)cn1

Procedure:
Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.080 g, 0.21 mmol) and 7-Amino-6-fluoro-3,4-dihydro-1H-quinolin-2-one were reacted in an analogous manner to Example 908D at 50° C. for 32 h. Upon completion, the product was triturated and washed with acetone. LC/MS: 404.9 (M+H); HPLC: 2.770 minutes, 99% purity. MP: 295° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.91 (s, 1H), 8.65 (s, 1H), 8.34 (d, J=9.9 Hz, 1H), 7.48-7.42 (m, 2H), 7.10-7.05 (m, 2H), 6.94-6.90 (m, 2H), 4.05 (s, 3H), 3.06 (t, 2H), 2.71 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14](Cl)(=O)=O)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Sn].Cl>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Product: COc1cc(OC)c(C(=O)O)cc1S
Temperature: 40 °C

Procedure:
145 g of 2,4-dimethoxy-5-chlorosulphonyl benzoic acid, 393 ml of acetic acid and 230.5 g of tin are placed in a 6 liter flask fitted with an agitator, a thermometer and a dropping funnel, and the thick suspension is heated to 40° C. 1,009 ml of hydrochloric acid (density 1.18) is added drop by drop while cooling so as to keep the temperature at from 40° to 45°. The reaction is exothermic. The suspension dissolves gradually, the more acid is added, but the tin salts are precipitated about midway through the adding process. When all the acid has been added the water bath is heated to 55°-60° until the tin has dissolved. 2 liters of water is added and the acid which has precipitated is drained and washed with 460 ml of 10% hydrochloric acid, then with water. It is immediately re-dissolved in water and the necessary soda, the solution is filtered with charcoal, and the acid is re-precipitated by adding concentrated hydrochloric acid. The precipitate is drained, washed with water and dried in an oven at 40°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:7]=[CH:6][N:5]=1.I[CH2:20][CH3:21].[Cl-].[NH4+]>O1CCCC1>[Cl:3][C:4]1[CH:9]=[C:8]([N:10]([CH2:20][CH3:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:7]=[CH:6][N:5]=1
Reactant: Fc1cccc(Nc2cc(Cl)ncn2)c1F
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(c1cc(Cl)ncn1)c1cccc(F)c1F
Temperature: 25 °C
Yield: 41.2 %

Procedure:
In 4.2 ml of tetrahydrofuran was suspended 0.12 g of sodium hydride (60% in oil), to which 0.8 ml of a tetrahydrofuran solution containing 0.5 g of 4-chloro-6-(2,3-difluorophenylamino)pyrimidine was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.8 ml of a tetrahydrofuran solution containing 0.48 g of iodoethane was slowly added dropwise at 0° C., followed by further stirring for 8 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.23 g of 4-chloro-6-(N-ethyl-N-(2,3-difluorophenyl)amino)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([NH:15][C:16]2[C:21]([C:22]3[N:30]=[C:29]([CH3:31])[N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][N:26]4C3CCCCO3)=[CH:20][C:19]([CH:38]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH3:39])=[CH:18][N:17]=2)=[CH:4][N:3]=1.Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+]>[OH-].[Na+].C1COCC1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:10])=[O:11])=[CH:6][C:5]([NH:15][C:16]2[C:21]([C:22]3[N:30]=[C:29]([CH3:31])[N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)=[CH:20][C:19]([CH:38]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH3:39])=[CH:18][N:17]=2)=[CH:4][N:3]=1
Reactant: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(=O)(=O)N(C)C)c2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(=O)(=O)N(C)C)c2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a 20 mL scintillation vial, N′-(2-chloro-5-((3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(1-(4-morpholinyl)ethyl)-2-pyridinyl)amino)-3-pyridinyl)-N,N-dimethylsulfamide (0.047 g, 0.072 mmol) and 5 N hydrochloric acid (0.5 mL, 2.5 mmol) were mixed into THF (2 mL). The solution was stirred at room temperature for 30 min. Buffer (pH 5, citric acid/NaOH) (10 mL) was added and the pH was further adjusted to about 5 using a few drops of 6 N NaOH. The aqueous phase was extracted with 10% isopropanol in chloroform (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford N′-(2-chloro-5-((3-(2-methyl-9H-purin-6-yl)-5-(1-(4-morpholinyl)ethyl)-2-pyridinyl)amino)-3-pyridinyl)-N,N-dimethylsulfamide (0.0237 g, 58% yield) as a yellow powder. 1H NMR (400 MHz, chloroFORM-d) δ ppm 13.10 (s, 1H) 11.17 (br. s., 1H) 9.81 (br. s., 1H) 8.86 (d, J=2.15 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H) 8.34 (d, J=1.37 Hz, 1H) 8.22 (s, 1H) 6.81 (br. s., 1H) 3.74 (br. s., 4H) 3.56 (d, J=6.65 Hz, 1H) 2.96 (s, 9H) 2.44-2.66 (m, 4H) 1.50 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion): 573.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(OCCO)C.O.[Cu].[Cu-]=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: Nc1ccccc1
Agent: O=[Cu-]
Agent: [Cu]
Agent: Cl
Solvent: O
Solvent: CCOCCO
Product: O=C(O)c1ccc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
A solution of 2-bromo-4-chlorobenzoic acid (25.0 g, 106.0 mmol) in 2-ethoxy ethanol (40 mL) was treated with copper powder (0.74 g, 11.6 mmol), copper (I) oxide (0.76 g, 5.3 mmol) and potassium carbonate (15.8 g, 114.0 mmol) at 25° C. under nitrogen. The reaction was stirred at 25° C. for 5 min. At this time, the reaction was treated with aniline (11.2 mL, 124 mmol) and then was heated 135° C. for 48 h. At this time, the reaction was cooled to 25° C., diluted with water (30 mL) and was acidified with a 1N aqueous hydrochloric acid solution. The resulting mixture was stirred at 25° C. overnight. At this time, the resulting precipitate was collected by filtration through a sintered glass funnel. The solids were washed with an excess amount of water (2×100 mL) and then were dried under high vacuum to afford 4-chloro-2-phenylamino-benzoic acid (19 g, 72.3%) as a brown solid. This material was used without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[O:69][N:68]=[CH:67][C:66]=1[C:70](O)=[O:71]>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:66]5[CH:67]=[N:68][O:69][C:65]=5[CH3:64])=[O:71])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: Cc1oncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2cnoc2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.8 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 5-methyl-4-isoxazolecarboxylic acid (0.127 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(5-methylisoxazol-4-yl)carbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.138 g). 1H NMR Spectrum: (DMSO d6 373K) 1.83 (m, 2H), 2.08 (m, 2H), 2.40 (s, 3H), 3.52 (m, 2H), 3.80 (m, 2H), 3.97 (s, 3H), 4.79 (m, 1H), 7.24 (m, 1H), 7.24 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 8.59 (s, 1H), 9.27 (br s, 1H); Mass Spectrum: (M+H)+ 512.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.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>[NH2:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:15][CH2:14][CH2:13][C@@H:12]3[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCC[C@@H]1CO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(-c2ccc(S(=O)(=O)N3CCC[C@@H]3CO)cc2)c1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
To a solution of (R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (1.6 g, 5.0 mmol) in DMF (10 mL) was added 3-amino-phenyl boronic acid (0.75 g, 5.5 mmol), Pd(PPh3)4 (45 mg, 0.15 mmol), potassium carbonate (0.75 g, 5.5 mmol) and water (5 mL). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20° C. The reaction mixture was then heated at 80° C. overnight. The reaction was filtered through a pad of silica gel, which was washed with CH2Cl2 (25 mL×3). The combined organics were concentrated under reduced pressure to give the crude product, which was washed with EtOAc to give pure (R)-(1-(3′-aminobiphenyl-4-ylsulfonyl)pyrrolidin-2-yl)methanol (C-2) (810 mg, 49%). NMR (300 MHz, CDCl3) δ 7.88 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.23-7.28 (m, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 6.74 (dd, J=7.8, 1.2 Hz, 1H), 3.66-3.77 (m, 3H), 3.45-3.53 (m, 1H), 3.26-3.34 (m, 1H), 1.68-1.88 (m, 3H), 1.45-1.55 (m, 1H). MS (ESI) m/e (M+H+) 333.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[O:44][C:43]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[C:42](I)[C:41]2=[O:57]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:42]3[C:41](=[O:57])[C:40]4[C:45](=[CH:46][C:47]([O:48][CH3:49])=[C:38]([Br:37])[CH:39]=4)[O:44][C:43]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1cc2oc(-c3ccccc3)c(I)c(=O)c2cc1Br
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1Br
Yield: 75 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 6-bromo-3-iodo-7-methoxy-2-phenyl-chromen-4-one was reacted to give the title compound as a pale yellow foam (434 mg, 75%). LCMS (Method B): RT=5.04 min, [M+Na]+=598/600.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br.[S:34]1[C:43]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38][C:37]=2[N:36]=[C:35]1[NH2:44].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[NH2:44][C:35]1[S:34][C:43]2[CH2:42][CH2:41][N:40]([C:21](=[O:22])[CH2:20][N:10]3[C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[CH:12][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9]3)[CH2:39][CH2:38][C:37]=2[N:36]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)cc1-c1ccc(F)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(s1)CCN(C(=O)Cn1nc(-c3ccc(F)cc3)cc1-c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
100 mg (3,5-bis-(4-fluoro-phenyl)-pyrazol-1-yl)-acetic acid was dissolved in 2 mL DMF. 165 mg PFTU and 170 μL DIPEA were added to this solution and the mixture was stirred for 15 min at RT. Then, 160 mg 5,6,7,8-Tetrahydro-4H-thiazolo (4,5-d) azepin-2-ylamine hydrobromide was added and the reaction was stirred over night. Then, K2CO3 solution (5%) and CH2Cl2 were added, the organic phase was separated and washed two times with water. The solvent was removed and the residue was purified by HPLC (method 1) to give 78 mg of the desired compound. Rt: 0.80 min (method C), (M+H)+: 466
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11](=[O:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:5][C:4]=1[O:18][CH3:19].[BH4-].[Na+]>>[CH3:20][N:2]([CH3:1])[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]([OH:17])[CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1N(C)C
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1N(C)C

Procedure:
A suspension of 24 g. of 4'-(dimethylamino)-3',5'-dimethoxy-2-(methylsulfonyl)-acetophenone and 12.1 g. of sodium borohydride in 260 ml. of alcohol was stirred at room temperature for 16 hours, whereby a solution was obtained. After the addition of 260 ml. of water, the alcohol was evaporated under vacuum. The precipitate was removed by filtration with suction, washed with water and recrystallized from ethyl acetate, whereby there was obtained 4-(dimethylamino)-3,5-dimethoxy-α-[(methylsulfonyl)-methyl]-benzyl alcohol having a melting point of 147°-148° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2.[Si:23]([O:30][CH2:31][CH2:32][CH2:33]Br)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O>[Si:23]([O:30][CH2:31][CH2:32][CH2:33][N:13]1[C:14]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:20]=[C:12]1[CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: COc1ccc2[nH]c(C=Cc3ccccc3Cl)cc2c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(C=Cc1ccccc1Cl)n2CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (1.05 g of a 50% dispersion in mineral oil, 0.022 mol) was added to a solution of the 2-[2-(2-Chlorophenyl)ethenyl]-5-methoxy-1H-indole prepared according to example 37 (4.13 g, 0.014 mol) in DMF (30 mL) and the solution was stirred at room temperature for 5 min. 3-Bromopropyl tert-butyl(dimethyl)silyl ether (4.04 g, 0.016 mol) was added and stirring was continued for 2 h. The solution was diluted with water, extracted with EtOAc which was washed well with brine and the organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give 1-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-2-[2-(2-chlorophenyl)ethenyl]-5-methoxy-1H-indole (28) as an oily solid (4.98 g) (as a mixture of E/Z isomers) which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:21][CH2:20][CH2:19][NH:1][C@@H:2]([CH2:3][C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@H](NCCO)C(=O)OC(C)(C)C

Procedure:
A solution of di-tert-butyl L-aspartate (5.62 g-20 mmol), 2-bromoethanol (2.84 ml-40 mmol) and K2CO3 (5.6 g-40 mmol) in 100 ml of acetonitrile is heated at reflux for 16 hours. The mineral salts are filtered off and the solvent is removed by distillation in vacuo. The crude product so obtained is purified by flash chromatography on silica gel using a (95/5) dichloromethane/ethanol mixture as eluant. The expected product is obtained in the form of a colourless oil.