Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([CH3:25])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C
Yield: 19 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14](I)[N:9]3[N:8]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14]([C:25]4[CH:26]=[C:21]([N:19]([CH3:20])[CH3:18])[CH:22]=[CH:23][CH:24]=4)[N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2nn3c(I)cnc3s2)cc1
Reactant: CN(C)c1cccc(B(O)O)c1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1cccc(-c2cnc3sc(Oc4ccc(F)cc4)nn23)c1
Temperature: 140 °C
Yield: 10.2 %

Procedure:
2-(4-Fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.13 g, 0.36 mmol) was suspended in 1,4-dioxane (1.5 mL) at room temperature and argon was bubbled into the mixture while tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.036 mmol), 3-(N,N-dimethylamino)phenylboronic acid (68 mg, 0.41 mmol), cesium carbonate (235 mg, 0.72 mmol, 2.0 eq), and water (1.5 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 1 hour. On cooling, the mixture was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 2:8). The obtained residue was crystallized from methanol:1,2-dichloroethane (1:1, 1.5 mL) and filtered to give {3-[2-(4-fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenyl}-dimethyl-amine as a white solid (13 mg, 10% yield).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>C(O)C>[N:15]1([C:2]2[C:11]([C:12]#[N:13])=[CH:10][C:9]3[C:8](=[O:14])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1cc2c(nc1Cl)CCCC2=O
Reactant: C1CCCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cc2c(nc1N1CCCCCC1)CCCC2=O
Yield: 38.2 %

Procedure:
A solution of 2-chloro-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.07 g, 0.34 mmol), azepane (0.07 g, 0.7 mmol) and triethylamine (0.052 ml, 0.07 g, 0.07 mmol) in ethyl alcohol (3 ml) was heated at reflux for 5 h. Then water (10 ml) was added and the precipitated solid was filtered off and recrystallized from ethyl alcohol to give the title compound (0.035 g, 38%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([CH3:22])=[CH:17][C:16]=2[N+:23]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([CH3:22])=[CH:17][C:16]=2[NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Yield: 80.5 %

Procedure:
A solution of 4-(5-fluoro-4-methyl-2-nitro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (680 mg, 1.92 mmol) and 10% Pd/C (68 mg) in ethanol (20 mL) was shaken under hydrogen (50 psi) for 4 hours. The reaction mixture was filtered through a pad of Celite® and the volatiles were removed. The residue was purified by flash chromatography (10% CH3OH in CH2Cl2) to afford 4-(2-amino-5-fluoro-4-methyl-phenylamino)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 80%) as an oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([OH:17])[C:11](=[CH:15][CH:16]=1)[C:12](O)=[O:13].O.Cl>C1COCC1.C(OCC)(=O)C>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[C:10]([OH:17])[CH:9]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 21 h
Yield: 70.4 %

Procedure:
To 7 g of LiAlH4 in 200 ml of THF is added portionwise 15 g of 4-chlorosalicylic acid. The resulting mixture is heated under reflux for one hour, cooled and stirred at room temperature for 21 hours. Water (7 ml) in THF (50 ml) is added dropwise, followed by 1N hydrochloric acid (250 ml), concentrated hydrochloric acid (50 ml) and ethyl acetate (200 ml). After filtration on a pad of celite the two layers are separated, the organic layer washed with brine, dried over magnesium sulfate, concentrated. The brown oil is dissolved in iso-propyl ether and filtered on a short column of silica gel. After concentration the solid is crystallized in cyclohexane, filtered, washed and dried to give 4-chloro-2-hydroxy-benzylalcohol as a white solid (9.7 g, 70% yield) C7H7ClO2 MS (M+) m/z: 158, 160, Cl pattern.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([OH:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:4]=1[OH:5])[CH3:2].S(=O)(=O)(O)O.[CH3:17][C:18](O)([CH2:20][CH:21](O)[CH3:22])[CH3:19]>C(OC(C)C)(C)C>[CH2:1]([C:3]1[C:4]([OH:5])=[CH:6][C:7]([CH3:11])=[C:8]2[C:9]=1[O:10][C:18]([CH3:19])([CH3:17])[CH2:20][CH:21]2[CH3:22])[CH3:2]
Reactant: CC(O)CC(C)(C)O
Reactant: CCc1c(O)cc(C)cc1O
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Product: CCc1c(O)cc(C)c2c1OC(C)(C)CC2C
Yield: 64.1 %

Procedure:
A mixed solution was prepared from 6.1 g. of 2-ethyl-5-methyl resorcinol, 40 ml of isopropyl ether and 2 ml of concentrated sulfuric acid. To this solution, 5.7 g. of 2-methylpentane-2,4-diol were added dropwise at about 60° C. for about 30 minutes. After cooling, this solution was successively washed with water, with aqueous 1 N sodium hydroxide solution and again with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by subjecting to column chromatography filled with silica gel. There were obtained 6.0 g. (yield: 64.1%) of the subject compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[N:9]1([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1
Reactant: COc1ccc(-n2ncc3ccccc32)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(-n2ncc3ccccc32)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
1-(4-Methoxyphenyl)-1H-indazole (30 mg, 0.134 mmol) was dissolved in dichloromethane (0.4 mL) and cooled to 40° C. Boron tribromide (0.4 mL, 1 M solution in dichloromethane, 0.4 mmol) was added, and the reaction was warmed to rt and stirred for 5 hours. Saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The extracts were dried over MgSO4 and concentrated to give the desired product. LC-MS (C13H10N2O calculated 210) m/z 211 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20](I)=[CH:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=3)=[CH:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(I)ccnc2c1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccnc3cc(Cl)ccc23)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (54 mg, 0.29 mmol) and 7-chloro-4-iodoquinoline (93 mg, 0.32 mmol) according to the general procedure IC to give 54 mg (54%) of a beige solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:4). Rf=0.06 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 8.88 (d, J=4.8 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.11 (m, 1H), 7.59-7.52 (m, 4H), 7.28-7.25 (m, 2H), 3.69 (s, 3H), 3.01 (t, J=7.8 Hz, 2H), 2.67 (t, J=7.8 Hz, 2H); 13C NMR (CDCl3) δ 172.9, 150.8, 148.5, 142.4, 135.8, 132.1, 129.9, 128.8, 128.6, 128.1, 127.4, 126.1, 123.5, 119.9, 99.2, 84.4, 51.7, 35.2, 30.9; ESI-MS m/z 372.1 (M+Na+).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]2[N:23]=[C:22]([CH:24]=[CH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32]C)=[C:28]([O:34]C)[CH:27]=3)[O:21][N:20]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]2[N:23]=[C:22]([CH:24]=[CH:25][C:26]3[CH:27]=[C:28]([OH:34])[C:29]([OH:32])=[CH:30][CH:31]=3)[O:21][N:20]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(C=Cc2nc(CC3CCN(Cc4ccccc4)CC3)no2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(C=Cc2nc(CC3CCN(Cc4ccccc4)CC3)no2)cc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Boron tribromide (0.056 mL, 0,595 mmol) was added drop wise to a cooled solution of 1-benzyl-4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-piperidine (compound of Example 30; 0.05 g, 0.12 mol) in dichloromethane (3 mL) at −78° C. The reaction mixture was warmed to room temperature and stirred for 6 h. The reaction mixture was quenched with methanol (2 mL) and the organic solvent was evaporated. The residue was suspended in methanolic ammonia (2 mL) and the undissolved solid was filtered. The filtrate was evaporated to obtain a crude product, which was purified by column chromatography (silica gel, 3% methanol in chloroform) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][C:7]([C:15]([OH:17])=O)=[CH:6]2.C(N(CC)CC)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH2:42][N:43]1[CH2:47][CH2:46][NH:45][C:44]1=[O:48]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][C:7]([C:15]([NH:42][N:43]1[CH2:47][CH2:46][NH:45][C:44]1=[O:48])=[O:17])=[CH:6]2
Reactant: COc1cc2cnc(C(=O)O)cc2cc1OC
Reactant: NN1CCNC1=O
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2cnc(C(=O)NN3CCNC3=O)cc2cc1OC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 6,7-dimethoxy-3-isoquinolinecarboxylic acid (6.99 g, 30.0 mmol) in 300 ml of N,N-dimethylformamide were added triethylamine (12.14 g, 120.0 mmol) and diphenyl chlorophosphate (80.6 g, 30.0 mmol) at 0° C. After stirring for 4 hours at 0° C., N-amino-2-oxoimidazolidine (3.03 g, 30.0 mmol) was added, and the mixture was stirred at 0° C. overnight. Ammonium salts (2.0 g) were filtered off, and the filtrate was evaporated in vacuo. The residue was triturated with a 1:1 mixture of water and ethyl acetate. The solid was filtered off and triturated twice with water at pH 8 for 3 hours. The remaining solid was filtered off, washed with water and dried in vacuo. Yield: 4.30 g; melting point 220° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[C:47]([CH3:48])=[CH:46][CH:45]=[CH:44][N:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[C:47]([CH3:48])=[CH:46][CH:45]=[CH:44][N:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cccnc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ncccc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 2-bromo-3-methylpyridine (35 mg) instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-08, a crude product of bis-(4-methoxy-benzyl)-{5-[7-(3-methyl-pyridin-2-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-amine was obtained, and then PMB group was removed according to the above Deprotection method 3, to obtain the desired compound (D-178) as a yellow solid (20 mg, 28%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1O.[OH-].[Na+]>O>[C:2]1([C:1]2[O:9][C:16]3[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 117.5 °C

Procedure:
PPA (160 g) is added to benzoic acid (14.26 g, 0.117 mol) and 2-amino-5-nitrophenol (20 g, 0.117 mol). The mixture is heated at 115-120° C. for 30 minutes and cooled, and water (200 ml) is added dropwise, followed by addition of 32% NaOH (pH=10). The product is filtered off, washed with water and filtered off. It is recrystallized from isopropyl ether. Yield: 25 g (90%); Elem. anal. C13H8N2O3; theory C, 65.00; H, 3.35; N, 11.66. found C, 64.56; H, 3.22; N, 11.43. IR (KBr): 1551, 1515, 1340 cm−1.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:33]12([NH:39]C(=O)OC(C)(C)C)[CH2:38][CH:37]1[CH2:36][NH:35][CH2:34]2>>[NH2:39][C:33]12[CH2:38][CH:37]1[CH2:36][N:35]([C:2]1[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:13][CH:14]=3)=[O:7])=[CH:4][N:3]=1)[CH2:34]2
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)NC12CNCC1C2
Product: NC12CC1CN(c1ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc1-c1ccn[nH]1)C2

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl 3-azabicyclo[3.1.0]hexan-1-ylcarbamate to afford an off-white foam. HPLC (Condition 4) tR=4.32 min, UPLC-MS (Condition 3) tR=0.79 min, m/z=461.1 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH3:16][C:17]1[C:22](/[CH:23]=[CH:24]/[CH:25]=[O:26])=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:20]=[C:19]([CH3:34])[N:18]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:16][C:17]1[C:22](/[CH:23]=[CH:24]/[CH:25]([OH:26])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:21]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH:20]=[C:19]([CH3:34])[N:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(-c2ccc(F)cc2)c(/C=C/C=O)c(C)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)cc(C)nc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
82.2 μl (0.76 mmol) of methyl acetoacetate are added dropwise at 0° C. under a nitrogen atmosphere to 18.5 mg (0.8 mmol) of sodium hydride in 1 ml of tetrahydrofuran. After 15 minutes, 0.55 ml (0.77 mmol) of n-butyllithium (1.5M in hexane) is added dropwise at 0° C., the mixture is stirred for 15 minutes at 0° C. and 180 mg (0.7 mmol) of the compound from Example 31 are added dropwise in 3 ml of tetrahydrofuran. After 1 h, the mixture is hydrolyzed using saturated ammonium chloride solution and washed three times using dichloromethane, and the organic phases are dried and 0.25 g of oil are obtained after removing the solvent in vacuo.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([O:12]S(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.C[Mg]Br>C(OCC)C>[CH:7]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
A solution of 1-(diphenylmethyl)-3-(methanesulphonyloxy) azetidine (1.0 g) in. THF (17 mL) was treated with 3.0 M methylmagnesium bromide (1.2 mL) in diethyl ether at 0° C. The reaction was stirred for 1.5 hours at 0° C. and then quenched with saturated aqueous sodium bicarbonate, filtered through Celite, and concentrated. The residue was then take up in methylene chloride and washed with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by column chromatography (0 to 60% EtOAc/hexanes) to provide 640 mg of the title compounds as a clear, yellow oil. ESMS: 240.19 (M+1), 1.22 minutes, Method D.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>>[OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(=NO)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(C(=NO)C(=O)O)cs1
Reaction time: 2 h

Procedure:
A solution of ethyl 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (1.1 g) in an 1N aqueous solution of sodium hydroxide (15 ml) was allowed to stand for 2 hours at ambient temperature. The reaction mixture was adjusted to pH 3.5 with 10% hydrochloric acid and precipitating crystals were collected by filtration, washed with acetone and dried to give 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (a mixture of syn and anti isomers) (0.52 g), mp 184° to 186° C. (dec.).
Reaction SMILES: [CH:1]1([C:7](=[O:13])[C:8]([O:10]CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Na+].Cl>CO>[CH:1]1([C:7](=[O:13])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)C1CCCCC1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of ethyl cyclohexyloxoacetate (46 g) in MeOH (25 mL) was added water (60 mL) and NaOH (50% 20 mL) at 0-15° C. The reaction mixture was heated to 60° C. for 1.5 h. The reaction mixture was cooled with ice-water bath, and acidified with 15% HCl till pH 1. The mixture was extracted with ethyl acetate (2×250 mL). The extracts were washed with brine, dried with sodium sulfate. The drying agent was removed by filtration and the solvent was removed to give a low melting solid (39 g, 99%). 1H NMR: δ 1.15-1.40 (m, 5H,), 1.62-1.96 (m, 5H). 3.20 (m, 1H), 9.4 (s, 1H). 13C-NMR δ 25.93, 25.76, 27.89, 45.04, 160.90, 198.29.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:32])[C:22]=1[N:23]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[N:24]1)[O:5][C@H:6]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].[OH-].[Na+].Cl.[CH2:36]([OH:43])[C:37]([NH2:42])([CH2:40][OH:41])[CH2:38][OH:39]>O.CO>[NH2:42][C:37]([CH2:40][OH:41])([CH2:38][OH:39])[CH2:36][OH:43].[CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:32])[C:22]=1[N:23]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[N:24]1)[O:5][C@H:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)O)cc1
Temperature: 35 °C
Yield: 77 %

Procedure:
To the solution from step 3 was added 5 M sodium hydroxide solution (29 mL, 145 mmol) and methanol (30 mL). The solution was heated to 35° C. for 6 h. After cooling to room temperature, the solution was acidified with conc. HCl (12.4 mL). The reaction was washed with water (30 mL). The organic solution was concentrated and the residue taken up in acetonitrile (100 mL). A solution of tris(hydroxymethyl)aminomethane (5.82 g, 48 mmol) in water (5 mL) was added slowly. The resulting slurry was cooled to 0° C. The product was filtered and washed with acetonitrile to give the desired salt as a white solid (20.5 g, 77% yield) 1H NMR (400 MHz, DMSO-d6) δ: 8.53 (s, 1H), 8.09 (s, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 6.74 (s, 2H), 5.38 (dd, J=7.4, 5.1 Hz, 1H), 3.37 (s, 6H), 1.94-1.85 (m, 1H), 1.79 (s, 6H), 1.76-1.68 (m, 1H), 1.45-1.29 (m, 2H), 0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The known compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-phenyl-methanone and 4-methoxy-benzenesulfonyl chloride and purified by flash chromatography (20% EtOAc.Hexane). 1H NMR (CDCl3) δ 9.63 (s, 1H) 7.75 (d, J=12 Hz, 1H) 7.57 (m, 3H) 7.49-7.35 (m, 5H) 7.33 (d, J=4 Hz, 1H) 6.69 (d, J=12 Hz, 2H) 3.67 (s, 3H). MS: m/z=402.0 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9](I)[N:8]([CH3:13])[C:7]=1[CH3:14])=[O:5])[CH3:2].[CH3:15][O:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:17]=2[O:16][CH3:15])[N:8]([CH3:13])[C:7]=1[CH3:14])=[O:5])[CH3:2]
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)c1c(C)c(I)n(C)c1C
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C)c(-c2cccc([N+](=O)[O-])c2OC)n(C)c1C
Temperature: 25 °C
Yield: 40.1 %

Procedure:
5-Iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6e (2.88 g, 9.38 mmol) was dissolved in 25 mL of 1,4-dioxane followed by addition of 2-(2-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 6a (3.6 g, 10.3 mmol), tetrakis(triphenylphosphine)palladium (270 mg, 0.234 mmol), sodium carbonate (1.99 g, 18.77 mmol) and 10 mL of water. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled to room temperature followed by addition of 30 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(3-nitro-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6f (1.25 g, yield 40.4%) as a yellow oil.