Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]2[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[S:12][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:20]1[CH:19]=[CH:18][C:11]2[S:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]=2[CH:21]=1
Reactant: COC(=O)c1sc2ccccc2c1-c1ccccc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Add 29.3 g. bromine (10 ml; 0.37 mole) to 8.0 g. (0.03 mole) of methyl 3-phenylbenzo [b]thiophene-2-carboxylate in 100 ml. of acetic acid and stir the mixture overnight at room temperature. Add a saturated solution of sodium bisulfite. Decant the supernatant and wash the oil with water. Triturate with methanol. Recrystallize from methanol to yield the title compound; m.p. 125°-126°.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.O=[CH:11][CH2:12][C:13]1([C:29](OCC)=[O:30])[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:14]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[OH:9][C@@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]2[CH2:11][CH2:12][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:20])[CH2:14]3)[C:29]2=[O:30])[CH2:4][CH2:5]1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CCCC2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a suspension of cis-4-aminocyclohexanol hydrochloride (Available from Sijia Medchem Lab, China) (13.8 g, 0.0910 mol) and 1-benzyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (31.0 g, 0.0930 mol) in 1,2-dichloroethane (250 mL) was added triethylamine (23.3 mL, 0.167 mol) at room temperature. The mixture was stirred at 40° C. overnight. Sodium triacetoxyborohydride (Aldrich, cat #: 316393) (49.3 g, 0.232 mol) was added to the above mixture and stirred at r.t. for 1 h. LC/MS data indicated that the starting material was consumed, and an intermediate product with m/e: 433.2 (M+H)+ was observed.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:5]1=2)#[N:2].Cl.C[O:23][C:24](=[O:30])[C@H:25]([CH:27]([CH3:29])[CH3:28])[NH2:26].C1COCC1.C([BH3-])#N.[Na+]>CO>[C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH2:19][NH:26][C@H:25]([C:24]([OH:23])=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:17]=[CH:18][C:5]1=2)#[N:2]
Reactant: N#CCN1c2ccccc2CCc2cc(C=O)ccc21
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@H](NCc1ccc2c(c1)CCc1ccccc1N2CC#N)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.6 %

Procedure:
A mixture of 1.0 g of Compound 40-a, 0.7 g of valine methylester hydrochloride, 0.5 g of molecular sieves and 15 ml of THF was stirred at room temperature for 2 days. After ice cooling, 3 ml of methanol and subsequently 0.4 g of sodium cyanoborohydride were added to the mixture. After the mixture was stirred overnight, insoluble matters were filtered off, and the filtrate was concentrated. The residue was diluted with dichloromethane, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The Solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (1/1)] to give 1.2 g (82%) of the product as a yellow oily substance.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@:5]([NH2:15])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:16])[C@:5]([NH:15][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@](C)(N)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@](C)(Cc1ccc(O)cc1)NC(=O)OCc1ccccc1

Procedure:
To a suspension of (S)-2-amino-3-(4-hydroxy-phenyl)-2-methyl-propionic acid methyl ester hydrochloride in ethyl acetate (25 mL) was added 1N NaHCO3 solution (12.5 mL) and the mixture was stirred rapidly at ambient temperature for the addition of neat benzyl chloroformate (1.01 eq.). Following addition, the reaction mixture was stirred for an additional hour; TLC and LCMS analysis showed the reaction to be complete. The mixture was partitioned and the organic phase was separated and dried over Na2SO4 and concentrated. The crude product was used directly in the subsequent reaction without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:14].O1CCCC1.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>CCCCCC>[CH2:9]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([B:25]([OH:30])[OH:26])=[C:3]([CH3:14])[CH:4]=1)([OH:13])[CH2:11][CH3:12])[CH3:10]
Reactant: CCC(O)(CC)c1ccc(Br)c(C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(B(O)O)c(C)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
In a three-necked flask, introduce under nitrogen 5 g of 3-(4-bromo-3-methylphenyl)pentan-3-ol (19.4 mmol) and 50 cm3 of tetrahydrofuran. Cool the mixture to −70° C. and add dropwise 23.3 cm3 (58 mmol) of a 2.5M solution of n-butyllithium in hexane, over 30 minutes. Leave the mixture for approximately 2 h with stirring at −70° C. and then add dropwise 13.5 cm3 of triisopropyl borate (58 mmol), over 20 minutes. Leave the mixture with stirring for 3 h, allowing the temperature to increase to −10° C. Hydrolyse the mixture with saturated NH4Cl solution and extract two times with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution and dry them over sodium sulfate. Evaporate the solvents under vacuum. This gives 5 g of a colorless oil, which is chromatographed on silica gel (heptane/ethyl acetate=9/1) to give 4-(1-ethyl-1-hydroxypropyl)-2-methylphenylboronic acid in the form of a highly viscous oil. (Yield=71%)
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].O[C:34]1[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37].C1CCC(N=C=NC2CCCCC2)CC1>CC#N.C1COCC1.CN(C1C=CN=CC=1)C>[C:1]([NH:24][CH:25]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:26]([O:28][C:41]1[CH:42]=[CH:43][CH:44]=[CH:34][C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)Oc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoic acid (50 mg, 0.11 mmol) and ethyl 2-hydroxybenzoate (19 mg, 0.11 mmol) in CH3CN/THF (1:1, 0.5 mL) at −10° C. was added DCC (12 mg, 0.11 mmol) and DMAP (1 mg). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EtOAc-PE, 0-20%) to afford ethyl 2-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate (40 mg, 67%) as colorless oil. Mass calculated for C37H51NO5=589.80; found: [M+H]+=590.4.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:25]=[C:24]([CH2:26][C:27]([NH:29][CH:30]([C:43]([OH:45])=[O:44])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:28])[CH:23]=[CH:22][C:11]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:8].CI>CN(C)C=O>[CH2:7]([O:9][C:10]1[CH:25]=[C:24]([CH2:26][C:27]([NH:29][CH:30]([C:43]([O:45][CH3:1])=[O:44])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:28])[CH:23]=[CH:22][C:11]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CCOc1cc(CC(=O)NC(C(=O)O)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOc1cc(CC(=O)NC(C(=O)OC)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (0.28 g, 2 mmol) is added to a solution of benzyl 2-ethoxy-4-[N-(α-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (1.06 g, 2 mmol) in anhydrous dimethyl formamide (8 ml). The mixture is stirred for 10 minutes at ambient temperature, then methyl iodide (0.125 ml, 2 mmol) is added and the resulting mixture is stirred overnight at ambient temperature. It is filtered and the filtrate is concentrated by evaporation to dryness in vacuo. The evaporation residue is partitioned between aqueous sodium bicarbonate solution (pH=9) and methylene chloride. The organic phase was poured over sodium sulphate, filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=4/1) and crystallised from ether/petroleum ether.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.C(O)(C)(C)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=1[S:44]([NH2:47])(=[O:46])=[O:45]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:47][S:44]([C:37]3[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:36]=3[Cl:35])(=[O:46])=[O:45])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Br)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Br)c3n2)c1
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
To the product of Step A (200 mg, 0.647 mmol) was added a solution of 4-(dimethylamino)pyridine (237 mg, 1.94 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (309 mg, 1.62 mmol) in a 1:1 mixture of t-butanol (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred for 15 min, 2-chloro-5-methoxybenzenesulfonamide (129 mg, 0.582 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was extracted with 1 N hydrochloric acid (3×100 mL), and the separated organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 234 mg of the title compound, a compound of the present invention, as a white solid, m.p. 191-192° C. 1H NMR (CDCl3) δ 10.1 (br s, 1H), 8.51 (s, 1H), 8.30 (s, 1H), 7.87 (d, 1H), 7.72 (s, 1H), 7.38 (d, 1H), 7.08 (dd, 1H) 3.91 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22]CC)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1.O>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([OH:22])=[O:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A solution of potassium trimethylsilanoate (0.141 g) in dry THF (5 ml) was added to a cooled solution of ethyl 2-benzenesulphonylamino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylate (Intermediate 1, 0.076 g) in dry THF (5 ml). The resultant cloudy solution was stirred at room temperature for 2 hours. Further potassium trimethylsilanoate (0.076 g) was added and the resultant mixture was stirred for a total of 72 hours. The mixture was then stirred and heated at 60° C. for a total of 48 hours. The resultant mixture was diluted with water and acidified to pH1 by addition of concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether. The solid was collected by filtration and air dried to give 2-benzenesulphonylamino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.034 g) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]2[CH:16]=[C:15]([CH2:17][N:18]([CH3:20])[CH3:19])[S:14][CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:22]>CO>[ClH:22].[ClH:22].[ClH:22].[CH3:20][N:18]([CH2:17][C:15]1[S:14][CH:13]=[C:12]([CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH:16]=1)[CH3:19]
Reactant: CN(C)Cc1cc(CSCCNC2=NS(=O)N=C2N)cs1
Agent: Cl
Solvent: CO
Product: CN(C)Cc1cc(CSCCNC(=N)C(=N)N)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A suspension of 3-amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide (7.8 g; 22.6 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 150 ml of methanol was treated with 15.0 ml of concentrated HCl. After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue triturated with 1-propanol, filtered and dried to give 7.38 g (80%) of product. A sample was recrystallized from methanol-acetone to give the title compound, mp 190°-205° C. (dec.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[N:14]1[CH:19]=[CH:18][C:17]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cn(-c2ccncc2)c2ccccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a vial containing methyl 1H-indole-3-carboxylate (402 mg, 2.297 mmol), pyridin-4-ylboronic acid (847 mg, 6.89 mmol), copper (II) acetate (542 mg, 2.99 mmol), 4 {acute over (Å)} molecular sieves (4 g) and 1,10-phenanthroline (828 mg, 4.59 mmol) were added DCM (9 ml) and triethylamine (0.320 ml, 2.297 mmol). The mixture was stirred at RT for 4 days then filtered through a pad of Celite (washed with MeOH). Evaporation and purification by HPLC (after dilution with DMF and filtration) afforded the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22](S(C)(=O)=O)[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:31][C:32]([NH2:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.[OH-].[Na+].O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:31][C:32]([NH2:34])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)N(c1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
30 mg of 4-(benzylamino)-6-({4-[bis(methylsulfonyl)amino]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 300) was dissolved in 3 mL of methanol, to which 1 mL of 4 mol/L sodium hydroxide in water was added at room temperature, and stirred at 50° C. for 10 minutes. Under ice cooling, 2 mol/L hydrochloric acid in water was added to acidify the solution, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 25 mg (99%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:15]([NH:25][C@H:26]([C:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:29])[CH3:27])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl N-benzyl-glycinate (47.5 g, 0.268 mol) and N-carbobenzyloxy-L-alanine (60.0 g, 0.268 mol) in 600 ml of methylene chloride at 0° C. was added dropwise a solution of N,N'-dicyclohexylcarbodiimide (55.2 g, 0.268 mol) in 600 ml methylene chloride over a 1 hour period. After the addition was complete the solution was stirred for 10 min., warmed to room temperature and continued stirring overnight. The solution was filtered, washed with dilute aqueous HCl, H2O, saturated NaHCO3, brine, dried (MgSO4). Concentration of the solution in vacuo yielded the oily product.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[C:44][C:45]3[CH:46]=[CH:47][C:48]([O:54][CH2:55][CH2:56][N:57]4[CH2:61][CH2:60][CH2:59][CH2:58]4)=[C:49]([CH:53]=3)[C:50]([OH:52])=O)=[N:41][CH:42]=2)=[CH:33][CH:32]=1.CN>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[C:44][C:45]3[CH:46]=[CH:47][C:48]([O:54][CH2:55][CH2:56][N:57]4[CH2:58][CH2:59][CH2:60][CH2:61]4)=[C:49]([CH:53]=3)[C:50]([NH:2][CH3:1])=[O:52])=[N:41][CH:42]=2)=[CH:35][CH:36]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg (0.25 mmol) TBTU and 69 μL triethylamine are added to a solution of 112 mg (0.25 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid (Example 22) in 5 mL DMF and the reaction mixture is stirred for 2 h at RT. Then 31 mg (1.0 mmol) methylamine are added and stirring is continued for a further 2 h at RT. The mixture is evaporated down i. vac., the residue is combined with dilute Na2CO3 solution, extracted exhaustively with DCM and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, DCM to DCM/MeOH/NH3 7:3:0.3).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1>>[F:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[F:33])[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Fc1ccc(OCCCBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)c(F)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.820 g of 4-(3-bromopropoxy)-1,2-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.65 (1:1 EtOAc-heptane); Rt=5.30.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.C(OC([N:33]([CH2:38][C:39]1[N:40]2[CH:46]=[N:45][CH:44]=[C:41]2[S:42][CH:43]=1)[S:34]([NH2:37])(=[O:36])=[O:35])=O)C=C>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:45]3[CH:44]=[C:41]4[S:42][CH:43]=[C:39]([CH2:38][NH:33][S:34]([NH2:37])(=[O:35])=[O:36])[N+:40]4=[CH:46]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: C=CCOC(=O)N(Cc1csc2cncn12)S(N)(=O)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(CNS(N)(=O)=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 2.5 %

Procedure:
The same procedure as in Example 1 was repeated except that 91.3 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 145 mg of 3-[N-allyloxycarbonyl-N-(aminosulfonyl)amino]methyl imidazo[5,1-b]thiazole were used, thereby obtaining 2.8 mg of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[C:20]1(=[O:24])[CH2:23][CH2:22][CH2:21]1>C1COCC1>[Br:13][C:14]1[C:19]([C:20]2([OH:24])[CH2:23][CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=C1CCC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC1(c2cccnc2Br)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a solution of diisopropylamine (3.0 mL, 21.40 mmol) in THF (10 mL) at −78° C. was added n-BuLi (7.6 mL, 17.84 mmol). After 30 min, a solution of 2-bromopyridine (1.1 mL, 11.89 mmol) in THF (30 mL) was added and stirring was continued at −78° C. After 45 min, cyclobutanone (1.0 g, 14.27 mmol) was added and the mixture was stirred at −78° C. for 1.5 h. After warming to room temperature, the mixture was quenched with water (20 mL), diluted with saturated NH4Cl (15 mL), and extracted with Et2O (3×30 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated to afford an orange oil. Purification by flash column chromatography on silica gel using hexanes/EtOAc (2:1) afforded 1-(2-bromo-pyridin-3-yl)-cyclobutanol as an orange oil (1.0 g, 37%). 1H NMR (CDCl3) δ 1.69-1.73 (m, 1H), 2.19-2.22 (m, 1H), 2.49-2.55 (m, 2H), 2.61-2.68 (m, 2H), 3.01 (s, 1H), 7.29 (dd, 1H, J=5.1, 4.8 Hz), 7.68 (dd, 1H, J=7.7, 2.1 Hz), 8.28 (dd, 1H, J=4.7, 1.8 Hz).