Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21](O)=[O:22])=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1>>[CH3:26][N:27]1[CH:31]=[C:30]([NH:32][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])=[CH:20][N:19]=2)=[O:22])[CH:29]=[N:28]1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reactant: Cn1cc(N)cn1
Product: Cn1cc(NC(=O)c2ccc(OCc3c(-c4ccc(F)cc4)noc3CO)cn2)cn1
Yield: 54 %

Procedure:
As described for example 34b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.22 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine instead of S-(+)-1-amino-2-propanol, to the title compound (50 mg, 54%), which was obtained as a colourless gum. MS: m/e=424.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N(CC)CC)C.C(=O)=O.CC(C)=O.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:31])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1C
Reaction time: 0.5 h

Procedure:
The N-methyl-5-aminoindole2-carboxylic acid ethyl ester (2.4 g, 11 mmol) was added with 100 ml of CH2Cl2 and triethyl amine (2.3 ml, 16.5 mmol). The reaction mixture was brought to −78 degree (dry ice-acetone) under N2. After (CF3SO2)2O (2.0 ml, 12 mmol) was added into it slowly via a syringe, the reaction mixture was stirred at −78 degree for 30 min and slowly brought to room temperature. The reaction was treated with 300 ml of CH2Cl2 and washed with Sat. Na2SO4 (100 ml×3), H2O (100 ml×50, and brine. TLC (20% EA/Hexane) showed two components, the desired product with smaller Rf value and the corresponding 5-(N,N-ditrifluoromethanesulfonyl)aminoindole. After the solvent was evaporated, the residue was purified either via recrystalization with CH2Cl2/Hexane or Flash Column (20% EA/Hexane). The purified product (1-Methyl-5-trifluoromethansulfonylamino-1H-indole-2-carboxylic acid ethyl ester) was obtained as a light orange solid (1.6 g). 1H-NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H, SNH-5), 7.64 (d, J=8.6 Hz, 1H, H-7), 7.60 (d, J=2.2 Hz, 1H, H-4), 7.31 (s, 1H, H-3), 7.23 (dd, J=2.2, 8.6 Hz, 1H, H-6), 4.33 (q, J=7 Hz, 2H, CH2CH3), 4.02 (s, 3H, NCH3), 1.33 (t, 3H, CH2CH3), MS m/z 349 [M−H].
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][CH:8]([Cl:13])[C:9]([F:12])([F:11])[F:10].[CH3:14][CH:15]([CH3:19])[CH:16]=[C:17]=[O:18].O1CCCC1>CN(C)C=O>[Br:7][C:8]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:17]([OH:18])[CH:16]=[C:15]([CH3:19])[CH3:14]
Reactant: CC(C)C=C=O
Reactant: FC(F)(F)C(Cl)Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Sodium t-butoxide (1.39 g of a 42% solution in dry dimethyl formamide was added dropwise over a period of 5 minutes to a stirred mixture of 1-bromo-1-chloro-2,2,2-trifluoroethane (0.535 ml), 3-methylbut-1-en-1-al (0.538 ml) and dry tetrahydrofuran (10 ml) maintained at a temperature of -78° C. by external cooling under a nitrogen atmosphere. The mixture was then stirred for a further 40 minutes at the temperature after which the external cooling was removed and the reaction quenched by the dropwise addition of saturated aqueous ammonium chloride solution. The mixture was then partitioned between water and diisopropyl ether and the aqueous phase separated, washed with diisopropyl ether (3×25 ml), and the washings combined with the organic phase. The organic phase was washed with brine and dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. After purification by a procedure similar to that set out in the previous Example there was obtained 5-bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene (1.39 g), identified by nuclear magnetic resonance and infra-red spectroscopy.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=O.B.C1COCC1>C1COCC1>[CH3:1][NH:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: O=CNCCN1CCCNCC1
Agent: B
Solvent: C1CCOC1
Product: CNCCN1CCCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.75 gm of N-(2-formamidoethyl)homopiperazine in 20 ml of dry THF under N2 is added carefully 60 ml of borane THF solution. After the addition is complete the reaction mixture is heated to reflux for 5 hours then stirred at room temperature overnight. The reaction mixture is quenched by the careful addition of 20 ml of 6N HCl followed by refluxing for 1 hour. The reaction mixture is cooled, 50 ml of water added and solid KOH added carefully to alkaline pH. Extraction with ether gives the desired product N-(2-methylamino) homopiperazine.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=O)(=[O:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:16]3[CH:15]=[C:14]([C:11](=[O:13])[CH3:12])[CH:22]=[CH:21][CH:20]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: CC(=O)c1cccc(C(=O)O)c1
Agent: N
Product: CC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-acetylbenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 2.72 (s, 3 H), 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 7.80 (t, J=8.1 Hz, 1 H), 8.31 (ddd, J=8.1, 1.4, 1.2 Hz, 1 H), 8.47 (ddd, J=8.1, 1.4, 1.2 Hz, 1 H), 8.59 (ddd, J=8.1, 2.0, 1.8 Hz, 1 H), 8.75 (dd, J=5.2, 1.6 Hz, 1 H), 8.81 (t, J=1.4 Hz, 1 H), 9.32 (dd, J=2.4, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=O)=[CH:11][CH:10]=2)[CH2:3]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C>ClCCl>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH:37][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:4]4[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]4)=[CH:19][CH:18]=3)[NH:35][N:36]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4C[C@@H](C)N[C@@H](C)C4)cc3)[nH]n2)cc(OC)c1
Yield: 50.2 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide was prepared following the procedure as for Example 155, but starting with ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (0.525 g, 2 mmol), 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.495 g, 2.00 mmol) and 2M trimethylaluminium (2.5 ml, 5.0 mmol in toluene). The crude mixture was chromatographed on a SCX column, eluting with 7N ammonia in methanol. Fractions containing product were combined and evaporated to give an oil. The oil was suspended in dichloromethane (20 ml) and product slowly crystallised out. This was filtered to give the title compound (0.465 g, 50.2%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1OCCCN1CCOCC1.Br[CH:28]([CH3:30])[CH3:29]>CN(C)C=O>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)Br
Reactant: COc1ccc(C#N)cc1OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1C(C)C
Temperature: 85 °C
Reaction time: 3 h

Procedure:
8 g Potassium carbonate and 2.7 g 3-hydroxy-4-methoxybenzonitrile (for synthesis see Example 47) was dissolved in 25 mL dimethylformamide. 2.15 mL 2-Bromopropane was added and the mixture stirred at 85° C. for 3 h. The mixture was concentrated, diluted in ethyl acetate and washed with water (×2) and saturated sodium chloride solution, dried over magnesium sulfate and concentrated.
Reaction SMILES: Cl.[C:2]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)C(OCC)=O)(=[O:4])[CH3:3]>>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:5][C:2](=[O:4])[CH3:3])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccncc1)C(C)=O
Agent: Cl
Product: CC(=O)CCc1ccncc1
Yield: 110.1 %

Procedure:
Next, 6 N hydrochloric acid (8 ml) was added to ethyl 2-acetyl-3-(4-pyridyl)propionate (1.20 g, 4.81 mmol), and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure, 2-propanol (10 ml) was added to the concentrate, and the whole was concentrated under reduced pressure again. Ethyl acetate was added to the resulting solid, and the solid was filtered off to give 4-(4-pyridyl)-2-butanone (0.79 g, 89%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C@H:15]([O:24][Si](CC)(CC)CC)[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][C:6]=2[CH:5]=1)[CH3:2].[ClH:41]>CO>[ClH:41].[CH2:1]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([NH:13][CH2:14][C@H:15]([OH:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)CC(N(C[C@@H](COc1ccccc1)O[Si](CC)(CC)CC)C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CO
Product: CCOc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2

Procedure:
A solution of N-(3-ethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (115 mg) and concentrated hydrochloric acid (0.5 ml) in methanol (5 ml) was stirred at room temperature for 48 hours. The mixture was evaporated in vacuo. The residue was triturated with diethyl ether-diisopropyl ether, followed by decantation and dryness in vacuo to give (2S)-1-(3-ethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol hydrochloride (30 mg).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:10]1(Br)[CH2:14][CH2:13][CH2:12][CH2:11]1.[O-]CC.[Na+]>C(O)C>[CH:10]1([CH:3]([C:2](=[O:1])[CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrC1CCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C(C)=O)C1CCCC1
Temperature: 22.5 °C
Yield: 71.6 %

Procedure:
A mixture of ethyl 3-oxobutanoate (0.5 mol), cyclopentyl bromide (0.5 mol) and sodium ethoxide (0.5 mol) in ethanol (100 ml) was heated under reflux for 15 hours. The reaction mixture was cooled to about 20-25° C., and 71 g of the title compound were then isolated by distillation (96-100° C., 0.25 mbar).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:38][CH3:39])[CH2:5][CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:30])[CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[C:11]3[S:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:9]([C:10]=23)=[N:8]1)[CH3:3].NN>CO>[ClH:1].[ClH:1].[NH2:19][CH2:18][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:7]([CH2:6][CH2:5][N:4]([CH2:2][CH3:3])[CH2:38][CH3:39])[N:8]=[C:9]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[S:31][C:11]=1[C:10]=23)=[O:30]
Reactant: CCN(CC)CCn1nc2c3c(c(NC(=O)CN4C(=O)c5ccccc5C4=O)ccc31)Sc1ccccc1-2
Agent: Cl
Agent: NN
Solvent: CO
Product: CCN(CC)CCn1nc2c3c(c(NC(=O)CN)ccc31)Sc1ccccc1-2
Reaction time: 48 h

Procedure:
A mixture of 3 g of N-[2-[2-(Diethylamino)ethyl]-2H-[1]benzothiopyrano[4,3,2-cd]indazol-5-yl]-1,3-dihydro-1,3-dioxo-2H-isoindol-2-acetamide, monohydrochloride, prepared as described in Example 96A, 0.784 ml of 54% aqueous hydrazine, and 40 ml of methanol was stirred for 2 days. The solution was then evaporated to dryness and the residue was diluted with water and extracted three times with 35-ml portions of ethyl acetate. The combined extracts were washed with 25 ml of saturated aqueous sodium carbonate solution and then dried over anhydrous magnesium sulfate. The ethyl acetate solutions were evaporated to afford the title compound as the free base. The dihydrochloride salt crystallizes from a methanolic solution of the free base upon acidification with 2.25 equivalents of hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][C@@H:32](O)[CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][C@@H:32]([CH2:33][CH3:34])[CH3:31])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: CC[C@@H](C)O
Product: CC[C@@H](C)OC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Yield: 68 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and (R)-butan-2-ol according to Method E (yellow solid, 155 mg, 0.326 mmol, 68% yield). ES-HRMS m/z calc. for C28H31ClN3O2 (M+H) 476.2099, found 476.2100.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7](N)[CH3:8])[CH:2]=1.[N:10]1[C:19]2[C:14](=CC=[CH:17][C:18]=2C(=O)C)C=CC=1.N.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:17][C:18]=2[CH:19]([NH2:10])[CH3:14])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)c1cccnc1
Reactant: CC(=O)c1cccc2cccnc12
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)c1cccc2cccnc12
Yield: 98 %

Procedure:
The title compound was prepared by the same procedure for preparing 1-pyridin-3-yl-ethylamine from 1-quinolin-8-yl-ethanone (1.71 g, 10 mmol), 2 M ammonia solution in methyl alcohol, acetic acid (25 mL, 50 mmol, Aldrich) and sodium cyanoborohydride (2.5 g, 40 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as light yellow solid in 98% yield (1.68 g, 9.8 mmol). MS (ESI, pos. ion) m/z: 173.2 (M+1); MS (ESI, neg. ion) m/z: 171.0 (M−1).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1.[Cl:22]N1C(=O)CCC1=O>ClCCl>[ClH:22].[Cl:1][C:11]1[CH:12]=[CH:13][C:14]2[O:15][C:16]3[C:21]([C:6]4([CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]4)[C:9]=2[CH:10]=1)=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCC2(CC1)c1ccccc1Oc1ccccc12
Agent: Cl
Solvent: ClCCl
Product: CN1CCC2(CC1)c1cc(Cl)ccc1Oc1ccc(Cl)cc12

Procedure:
A mixture of 1'-methylxanthene-9-spiro-4'-piperidine hydrochloride (5 g.), N-chlorosuccinimide (4.5 g.) and dichloromethane (100 ml.) is refluxed for 72 hours. The solution is washed with saturated sodium bicarbonate solution then water and dried with MgS04. The solution is evaporated to give a gummy residue which is chromatographed on grade 3 aluminium oxide, Woelm basic. The product is eluted with 30% petroleum-ether (b.p. 60°-80° C.)/chloroform, taken up in ether and the solution treated with ethereal hydrochloric acid. The precipitate is filtered and recrystallised from ethanol-ether to give 2,7-dichloro-1'-methylxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 285° C.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[N:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[N:14][CH:15]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)[C@H]1CCN(c2ccc(Br)cn2)C1
Temperature: 25 °C
Yield: 50 %

Procedure:
Heat a mixture of dimethyl-pyrrolidin-3-(S)-yl-amine (3.0 g, 26.3 mmoL), 5-bromo-2-fluoro-pyridine (4.62 g, 26.3 mmol), potassium carbonate (7.98 g, 57.8 mmol) in acetonitrile (91 mL) at 80° C. overnight. Allow the mixture to cool to RT, filter with CH2Cl2, and concentrate. Purify the crude material by flash chromatograph, eluting with 5% MeOH (2N NH3)/CH2Cl2 to give 3.55 g (50%) of the title compound. LC-MS/ES m/z (81Br) 272.3 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[CH:23]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])C.[OH-].[Na+]>>[C:41]([CH2:40][CH2:39][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:46])=[O:3])([OH:43])=[O:42]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccsc3)c2)c1CCC(=O)O
Yield: 89.8 %

Procedure:
A similar procedure as described in Example 12, step 9 was used, starting from 4-{2-(2-ethoxycarbony-ethyl)-3-[6-(3-pyridin-4-yl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (114 mg, 0.18 mmol) and 1.0 N aqueous NaOH (6 mL) to afford 4-{2-(2-carboxy-ethyl)-3-[6-(3-pyridin-4-yl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid (95 mg, 91%) as an amorphous white solid: ES(+)-HRMS m/e calculated for C34H37NO6S (M+H)+ 588.2415, found 588.2414.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C:8]2[CH:17]=[C:16](B(O)O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.Br[C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][N:27]=[CH:28]2.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C:8]2[CH:17]=[C:16]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][N:27]=[CH:28]4)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: Brc1cccc2cnccc12
Reactant: OB(O)c1cc(-c2cc(Cl)ccc2F)nc2ncccc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cl)cc1-c1cc(-c2cccc3cnccc23)c2cccnc2n1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A slurry of 151 mg (0.50 mmol) 2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 84.9 mg (0.40 mmol) 5-bromoisoquinoline and 44.4 mg (0.53 mmol) sodium bicarbonate in 2 ml DMF and 1 ml water was heated to 80° C. under nitrogen. Then 16.3 mg (0.02 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The reaction mixture was stirred for 18 hours at 80° C. Water was then added to the reaction mixture and the resulting precipitate was filtered off. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-(5-chloro-2-fluoro-phenyl)-4-isoquinolin-5-yl-[1,8]naphthyridine as colourless crystals: HPLC/MS: 2.10 min, [M+H] 386.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=O)[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO>[NH2:28][C@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[OH:1])[CH2:12]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: C[C@]12CC[C@H](N)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3β-Amino-17β-hydroxy-5α-androstane was prepared by the procedure of Boutigue et al. (1973, Bull. Soc. Chim. France 750-753). 17β-Hydroxy-5α-androstan-3-one (403 mg, 1.39 mmol) (Aldrich Chemical Company) was added to 862 mg of ammonium acetate (11.2 mmol, 8.06 equiv.) in 16.0 mL dry methanol (MeOH), followed by 104 mg (1.65 mmol, 1.19 equiv.) of sodium cyanoborohydride. After stirring at room temperature for 15 h, the reaction was concentrated under reduced pressure. The residue was partitioned between methylene chloride and aqueous 1N sodium hydroxide (NaOH), shaken, and separated. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)cn1
Temperature: 23 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23° C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79%). mp<50° C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6 H), 5.19 (s, 2H).
Reaction SMILES: CCCCCCCC[N:9]1[S:14][CH:13]=[CH:12][C:10]1=O.[P:15]([O-:19])([O-:18])([O-:17])=[O:16]>>[P:15]([O-:19])([O-:18])([O-:17])=[O:16].[S:14]1[CH2:9][C:10](=[O:16])[CH:12]=[N:13]1
Reactant: CCCCCCCCn1sccc1=O
Agent: O=P([O-])([O-])[O-]
Product: O=C1C=NSC1

Procedure:
1.0 M Phosphate buffer was prepared and 30 mL aliquots were adjusted to the following pHs: 3, 7, 10, and 12. 22.2 uL of 1000 ppm KATHON® 886 MW biocide was added to a semi micro cuvette followed by 2.065 mL of one of the above phosphate buffers. These preparations resulted in a final isothiazolinone concentration 10 ppm. The solution was mixed and allowed to stand for one minute before measuring the absorbance spectrum from 250 nm to 500 nm. Additional spectra were obtained until no notable change between subsequent spectra was observed.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([Cl:14])[N:13]=1)=[O:7])CCC.[NH2:19][CH2:20][C:21]([OH:23])=[O:22].CO[Na].CO>>[Cl:14][C:12]1[N:13]=[C:8]([C:6]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:7])[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]=12
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(Cl)c2sccc2c1O
Agent: CO[Na]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(Cl)c2sccc2c1O
Reaction time: 24 h
Yield: 96.3 %

Procedure:
A mixture of 7-chloro-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (143 mg, 0.5 mmol), glycine (751 mg, 10 mmol), and a 0.5 M solution of MeONa in methanol (20 ml, 10 mmol) was refluxed with stirring for 24 h before it was concentrated in vacuo. To the residue was added H2O (10 ml) and the pH of the mixture was adjusted to 1 to 2 by addition of 6 N HCl. The resulting suspension was extracted with EtOAc (1×25 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (138 mg). MS-(−)-ion: M−1=285.0.