Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH2:15]([C@@:18]1([CH3:45])[CH2:23][C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[C@@H:21]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[N:20]([C@@H:38]([CH2:42][CH3:43])[C:39](=[O:41])[CH3:40])[C:19]1=[O:44])[CH:16]=[CH2:17]>C1COCC1>[CH2:15]([C@@:18]1([CH3:45])[CH2:23][C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[C@@H:21]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[N:20]([C@@H:38]([CH2:42][CH3:43])[C@@H:39]([OH:41])[CH3:40])[C:19]1=[O:44])[CH:16]=[CH2:17]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)=O)C1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)[C@H](C)O)C1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
L-Selectride™ (1M in THF, 5.24 ml, 5.24 mmol) was added to a solution at −10° C. of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one (Example 149, step A, 2 g, 4.36 mmol) in THF (29.1 ml) being careful to maintain the temperature below −7° C. The reaction was stirred for 40 min then quenched into an aqueous solution of Oxone™ (10.73 g, 17.45 mmol) in 60 mL water. It was noted that the temperature spiked up to 40° C. during the addition. The reaction was cooled to RT using a water/ice bath and stirred at RT for 1 h, then diluted with ethyl acetate. The layers were separated and the aq layer was extracted with ethyl acetate. The combined organics were washed with brine and dried over MgSO4, filtered and concentrated. The crude material was dried under high vacuum overnight. Purification by column chromatography using 10-20% acetone in hexanes afforded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](#[N:17])[CH2:14][C:15]#[N:16].C1COCC1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:9][C:8]([C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[C:14]([C:13]#[N:17])[C:15]#[N:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: N#CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#CC(C#N)=C(O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
4-Nitrobenzoyl chloride (93 g, 0.50 mol) and malononitrile (33 g, 0.50 mol) were dissolved in toluene (400 mL) and THF (70 mL) in a flask equipped with an addition funnel, a thermometer, a stir bar, and argon atmosphere. The flask was immersed in a −30° C. bath. When the internal temperature reached −10° C., DIPEA (129 g, 1.0 mol) in 300 mL of toluene was added dropwise over 40 min. After an additional 1 hr, the bath was removed. After ca. 14 hr, the mixture had 2 layers. The bottom layer was concentrated in vacuo, dissolved in 400 mL of EtOAc, washed with 10% aqueous citric acid (2×250 mL), dried over Na2SO4, and concentrated in vacuo. The residue was mostly dissolved in THF (100 mL) and left 30 min in a freezer. The resulting solid was collected with the aid of additional freezer-cold THF and pressed well with rubber dam. The isolated solid (60 g) was suspended in 1 M H2SO4, collected, pressed, and washed with water. After drying, the solid weighed 36 g. This solid was dissolved in EtOAc (400 mL), washed with 1 M H2SO4 (200 mL) and water (200 mL), filtered through phase separation paper, and concentrated. The solid residue was reconcentrated successively from dichloromethane and toluene and dried at high vacuum. At this stage, 25 g were isolated. The HPLC purity was 94%. Analysis of a 60 MHz NMR spectrum showed about 18 mol % DIPEA. The material was used in the next step without further purification. Another 15 g portion of solid of 95% HPLC purity but containing 30 mol % DIPEA was eventually isolated from the THF filtrate. This material was set aside. The estimated overall yield of the reaction was about 42% NMR (60 MHz) (CDCl3) δ 8.0 (AB, 4H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S-:32].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([S:32][CH3:31])=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A solution of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.22 mmol) and sodium thiomethoxide (30 mg, 0.44 mmol) in DMF was heated at 100° C. in a sealed tube under nitrogen for 1 h. More sodium thiomethoxide (15 mg, 0.22 mmol) was added, and the heating pursued for 1 h. The mixture was left to cool to RT and was then partitioned between a sat. sodium carbonate solution and EtOAc. The organic layer was isolated, dried (MgSO4) and evaporated to dryness to afford 4-(2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (100 mg, 98%).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[N:19][C:4]1=2)[CH3:2].[C:25]([O-])(=[O:27])[CH3:26].[K+]>C(OC(=O)C)(=O)C>[C:25]([N:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[CH:16][C:5]3[N:6]([CH3:15])[C:7](=[O:14])[C:8]4[CH:13]=[CH:12][CH:11]=[N:10][C:9]=4[N:3]([CH2:1][CH3:2])[C:4]=3[N:19]=2)[CH:24]=[N:23]1)(=[O:27])[CH3:26]
Reactant: CC(=O)[O-]
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cn[nH]c3)nc21
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cnn(C(C)=O)c3)nc21

Procedure:
The title compound (mp 186°-188° C.) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-(4-pyrazolyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one by heating in acetic anhydride under reflux for 1 hour in the presence of potassium acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[K+].Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Br)cc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
Methyl 5-bromo-2-methoxybenzoate (14.7 g) obtained in step A was dissolved in 100 mL of methanol. To the solution, 40 mL of a 20% aqueous solution of potassium hydroxide was added, and the mixture was stirred for 2 hours at 80° C. The reaction solution was cooled to 0° C., and then adjusted to pH of about 3 with the use of 11 mL of concentrated hydrochloric acid. The precipitate was separated by filtration, washed with water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 10.9 g (85%) of 5-bromo-2-methoxybenzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][C:25]=1[O:32][CH3:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:6]2[CH:7]=[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]([O:3][CH2:1][CH3:2])=[N:5]2)=[CH:26][C:25]=1[O:32][CH3:33])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(CCl)ccc1OCc1ccccc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (1.59 g), 4-benzyloxy-3-methoxybenzyl chloride (1.97 g), and N,N-dimethylformamide (30 ml), sodium hydride (60%, oily, 0.30 g) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-(4-benzyloxy-3-methoxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionate (2.93 g, yield: 89%) was obtained as a colorless oily substance from the fractions eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.C([Li])CCC.[CH:20]1[N:24]=[CH:23][N:22]2[CH2:25][CH2:26][C:27](=[O:28])[C:21]=12.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C>[OH:28][C:27]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]3)[C:21]2[N:22]([CH:23]=[N:24][CH:20]=2)[CH2:25][CH2:26]1
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: O=C1CCn2cncc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Temperature: -100 °C
Reaction time: 0.17 h
Yield: 12.2 %

Procedure:
6-Bromo-2-naphthoic acid (1.51 g) was dissolved in dry THF (50 ml), and cooled to −100° C. in a liquid nitrogen/diethyl ether bath. Under stirring a solution (1.6M; 7.88 ml) of n-butyllithium in hexane was added dropwise at −95° C. or below over 5 min. After stirring at −100° C. for 30 min and at −80° C. for 10 min, the mixture was cooled to −100° C. again. A solution of 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (0.61 g) in dry THF (11 ml) was added dropwise at −90° C. or below over 5 min. After stirring at the same temperature for 30 min, the temperature was raised to −70° C. over 30 min, and saturated aqueous ammonium chloride solution (25 ml) was added to quench the reaction. After stirring for 10 min, ethyl acetate (50 ml) was added to partition the solution. The organic layer was removed and the aqueous layer was concentrated to dryness. The obtained residue was purified by flash column chromatography, and the object fraction was dissolved in methanol. This solution was concentrated, ether was added to the precipitated powder and the powder was collected by filtration and dried. The title compound (180 mg) was obtained as a colorless powder. The mother liquor was concentrated to give a residue (449 mg) containing the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>O1CCCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@H:2]([NH:1][S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[Cl:30])(=[O:39])=[O:38])[CH2:10]3)[CH:16]=1
Reactant: N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
(S)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.064 mmol, 20 mg) was dissolved in tetrahydrofuran (1 mL) and triethylamine (0.128 mmol, 17.8 μL) followed by 2-chlorobenzenesulfonyl chloride (0.064 mmol, 13.6 mg) and the solution stirred at room temperature overnight. The reaction was concentrated to dryness to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give the title compound (17.4 mg, 0.036 mmol, 56.0%) MS (ESI): m/z [M−H]− 484.5.
Reaction SMILES: C(OC([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>CN(C=O)C>[C:16]1([C:13]2[N:12]=[C:11]([CH2:10][CH2:9][NH:8][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[N:15]([CH2:41][C:42]([F:45])([F:44])[F:43])[N:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)n[nH]1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1nc(-c2ccccc2)nn1CC(F)(F)F
Reaction time: 0.33 h

Procedure:
5-[2-Bis(tert-butoxycarbonyl)aminoethyl]-3-phenyl-[1,2,4]triazole (200 mg, 515 μmol; example 22, step 1) was dissolved in DMF (3.57 mL) and potassium carbonate (157 mg, 1.14 mmol) was added at RT. The mixture was stirred for 20 min, 2,2,2-trifluoroethyl trifluoromethanesulfonate (165 mg, 710 μmol) was added and stirring was continued at RT overnight. The reaction mixture was extracted with ethyl acetate (40 mL) and washed with water (3×20 mL) and brine (1×20 mL). The aqueous layers were back-extracted with ethyl acetate (40 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as white solid (140 mg, 378 μmol, 73.4%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.C(O)(=O)C.[Br:13][C:14]1[C:20]([CH3:21])=[CH:19][C:17]([NH2:18])=[C:16]([O:22][CH3:23])[C:15]=1[F:24]>[Cl-].[Na+].O>[Br:13][C:14]1[C:20]([CH3:21])=[C:19]([I:1])[C:17]([NH2:18])=[C:16]([O:22][CH3:23])[C:15]=1[F:24]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1c(N)cc(C)c(Br)c1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(N)c(I)c(C)c(Br)c1F
Temperature: 25 °C
Reaction time: 67 h

Procedure:
N-iodosuccinimide (1.91 g, 8.5 mmol) was added to an acetic acid (40 ml) solution of 4-bromo-3-fluoro-2-methoxy-5-methylaniline (I-43) (1.90 g, 8.1 mmol), followed by stirring at room temperature for 67 hours. Saturated brine was added to the reaction liquid, followed by extraction twice with ethyl acetate, the organic layer was washed three times with saturated brine, dried over anhydrous magnesium sulfate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([O:22][Si](C)(C)C)[C:20]#N)[CH:14]=1.BrC[C:29]1[CH:41]=[CH:40][C:32]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1.CCCCCC>[O:22]=[C:19]([C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)[CH2:20][C:29]1[CH:41]=[CH:40][C:32]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)OC(C#N)c1cccnc1
Reactant: CCOC(=O)COc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(CC(=O)c2cccnc2)cc1
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
In argon atmosphere, 7.60 g of diisopropylamine was dissolved in 100 ml of dry tetrahydrofuran, followed by dropwise addition of 1.55M n-butyl lithium in 48.4 ml of hexane in solution at -20° C., which was then agitated at the same temperature for 15 minutes, subsequently followed by cooling to -78° C. and by subsequent dropwise addition of 15.48 g of 2-(3-pyridyl)-2-(trimethylsiloxy)acetonitrile dissolved in 150 ml of dry tetrahydrofuran over 10 minutes. After agitation at the same temperature for 30 minutes, the addition of 20.50 g of ethyl 4-(bromomethyl)phenoxyacetate dissolved in 30 ml of tetrahydrofuran over 10 minutes, the temperature was gradually raised from -78° C. to room temperature, followed by stirring overnight. Then, 1.0M tetra-n-butylammonium fluoride in 75.1 ml of tetrahydrofuran in solution was added, followed by agitation for five hours. To the resulting reaction mixture was added aqueous saturated solution of sodium chloride, followed by separation of the organic phase, which was then extracted with ethyl acetate from aqueous phase. The organic phases were combined, then washed in aqueous saturated solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, to yield 13.20 g of ethyl 4-[2-oxo-2-(3-pyridyl)ethyl]phenoxyacetate from a fraction eluted with methanol-chloroform (2:98 v/v).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[OH:7][CH2:8][CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].N1C=CC=CC=1>C(OCC)C>[Br:1][CH:2]([CH3:6])[C:3]([O:7][CH2:8][CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[O:4]
Reactant: CCOC(=O)NCCO
Reactant: CC(Br)C(=O)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)NCCOC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 32.4 g of 2-bromopropionyl bromide in 70 ml of diethyl ether is added dropwise within one hour while cooling with ice to a solution, cooled to 0° C., of ethyl 2-hyroxyethylcarbamate and 13.1 g of pyridine in 80 ml of diethyl ether. The reaction mixture is then stirred at room temperature for 45 minutes. For the working-up, the mxture is filtered under suction through Celite and the filtrate is poured into water. The aqeuous phase is extracted twice with diethyl ether, and the combined organic phases are washed twice with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated to dryness. There is obtained ethyl 2-(2-bromopropionyloxy)-ethylcarbamate as a colourless oil which either can be used in the reaction without further purification or can be purified further by chromatography on silica gel with n-hexane/diethyl ether (1:1); nD20 1.4770.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:2]=1.Cl.C(OCC)C>O1CCOCC1.O1C=COC=C1>[NH:13]1[CH2:12][CH2:11][CH:10]([N:3]2[C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[N:1]=[CH:2]2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3ccncc32)CC1
Agent: C1=COC=CO1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1cc2ncn(C3CCNCC3)c2cn1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(3H-imidazo[4,5-c]pyridine-3-yl)piperidine-1-carboxylate (1.12 g) in 1,4 dioxan (10 ml) was added 4M hydrochloric acid in dioxin (10 ml) and the resulting mixture was stirred for 3 hours. Diethyl ether (30 ml) was added and the mixture was filtered and washed with diethyl ether (50 ml) to give the title compound which was used without further purification. Yield 1.1 g. NMR (d6 DMSO) 2.35 (m, 2H), 2.5 (m, 2H), 3.1 (m, 2H), 3.5 (m, 2H), 5.05 (m, 1H), 8.3 (d, 1H), 8.65 (d, 1H), 9.3 (bd, 2H), 9.9 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:26][CH2:24][CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCN
Reactant: COC(=O)Cc1ccc(OC)c(-c2cc(OC)ccc2C=O)c1
Product: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]2[CH:18]=[CH:19][O:20][C:16]=2[C:15]=1[NH:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.O[CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]2[CH:18]=[CH:19][O:20][C:16]=2[C:15]=1[NH:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:38][CH2:39][N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: OCCN1CCCC1
Reactant: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
Diethyl azodicarboxylate (0.101 ml) was added dropwise to a stirred mixture of 4-(6-chlorobenzofuran-7-ylamino)-7-hydroxy-6-methoxyquinazoline (0.1 g), 1-(2-hydroxyethyl)pyrrolidine (0.04 g), triphenylphosphine (0.169 g) and methylene chloride (5 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.033 g) as a solid; NMR Spectrum: (DMSOd6 and CF3CO2D) 1.9 (m, 2H), 2.1 (m, 2H), 3.2 (m, 2H), 3.65-3.85 (m, 4H), 4.05 (s, 3H), 4.6 (m, 2H), 7.15 (d, 1H), 7.45 (s, 1H), 7.6 (d, 1H), 7.8 (d, 1H), 8.1 (d, 1H), 8.25 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 439.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]1[S:15][C:13](=[O:14])[NH:12][C:10]1=[O:11]>[O-2].[O-2].[Mn+4]>[CH:1](=[C:9]1[S:15][C:13](=[O:14])[NH:12][C:10]1=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C1NC(=O)C(=Cc2ccccc2)S1

Procedure:
The sulfonamide derivatives 2-5 and 2-6 are prepared as depicted in Scheme 2. The bis-aryl iodonium tetrafluoroborate 2-1 is coupled with 4-hydroxybenzoate 1-2 at room temperature in dichloromethane in the presence of copper bronze and a suitable base such as triethylamine (TEA) to afford diaryl ether 2-2. Reduction of ether 2-2 with DIBAL furnishes the corresponding alcohol which is oxidized to benzaldehyde 2-3 with manganese dioxide. Condensation of aldehyde 2-3 with thiazolidinedione produces an intermediate benzylidene thiazolidinedione which is hydrogenated to furnish benzyl thiazolidinedione 2-4. A subsequent chlorosulfonylation reaction yields a 3′-sulfonyl chloride which is then reacted with a primary or secondary amine to afford 3′-sulfonylamide 2-5. Demethylation of 2-5 with boron tribromide gives hydroxysulfonamide 2-6.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (489 mg) in THF (5.0 mL) and methanol (2.5 ml) was added 1N aqueous sodium hydroxide solution (5.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure, and the obtained solid was washed with diisopropyl ether to give the title compound (336 mg) as a white solid.