Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>CN(C=O)C.O>[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(Br)C(=O)OCC
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(C(=O)OCC)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
To a solution of diethyl malonate (8.01 g; 50 mmol) in dry DMF (25 mL) under nitrogen atmosphere was added potassium carbonate (7.6 g; 55 mmol), which has been dried at 120° C. for 12 h before using. After stirring for 15 min at room temperature, ethyl 2-bromovalerate (8.53 mL; 50 mmol) was slowly added under nitrogen and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture was poured in water (240 mL) and neutralized by adding a solution of hydrochloric acid 6N. The product was extracted with diethyl ether (2x240 mL) and the combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by distillation under reduced pressure furnished 12.8 g (99%) of the title compound as a colorless liquid (bp. 117° C., 2 mbar, temperature of the oil bath 165° C.).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:29][NH:30][CH3:31]>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14][N:30]([CH3:31])[CH3:29])=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: CNC
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CCCN(C)C)c(=O)n(CC3CC3)n2)cc1F
Yield: 64.7 %

Procedure:
Following the procedure of Example 7, 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow powder (yield: 64.7%).
Reaction SMILES: [O:1]=[C:2]1[CH2:20][CH2:19][C:18]2=[CH:21][N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=32)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:22][CH:23]([CH3:37])[CH2:24][CH:25]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27].O[N:39]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[CH2:29][CH:25]([C:26](=[O:27])[NH:39][C@H:20]1[CH2:19][C:18]2=[CH:21][N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=32)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:1])[CH2:24][CH:23]([CH3:37])[CH3:22])([CH3:36])([CH3:35])[CH3:34]
Reactant: On1nnc2ccccc21
Reactant: O=C1CCc2cn(c3ccccc23)CCCCCCCN1
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reaction time: 8 h

Procedure:
To a stirred solution of (11S)-11-amino-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraene (654 mg) and racemic 4-methyl-2-t-butoxycarbonylmethylpentanoic acid (800 mg) in 30 mL of anhydrous DMF under argon was added 1-hydroxybenzotriazole (360 mg), followed by EDCI (940 mg). The mixture was left to stir overnight and then the DMF was removed under reduced pressure. The residue was taken up in a mixture of CH2Cl2 (100 mL) and 1.5% cold HCl (100 mL) and transferred to a separatory funnel. The organic phase was isolated and washed consecutively with 1.5% HCl (100 mL), 5% NaHCO3 (100 mL) and brine (100 mL). The CH2Cl2 phase was dried (MgSO4), filtered and concentrated providing a semicrystalline product, (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid t-butyl ester. The two individual stereoisomers of this compound were separated by chromatography on silica gel with ethyl acetate/hexane as eluant. The less polar stereoisomer had a melting point of 154°-157° C., [α]D24 43.9°, c=23.8 mg/2 mL CHCl3, while the more polar stereoisomer had a melting point of 168°-171° C., [α]D24 =-19.1°, c=11.86 mg/2 mL CHCl3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:25]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>ClCCCl>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][C:7]=3[S:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:16]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To 671.4 mg of 6-methoxy-2-[4-[2-(1-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) in 10 mL of 1,2-dichloroethane was added 1.114 g of AlCl3 at 0° C., followed by dropwise addition of 0.30 mL of 4-fluorobenzoyl chloride. The deep red solution was stirred at 0° C. for 1 h and then at 0 to 15° C. for 19 h. The reaction was quenched by pouring the reaction mixture into 50 mL of ice-cold 2.0 N NaOH solution. The mixture was then extracted with 3×100 mL of EtOAc which was washed with 50 mL of H2O and brine. Combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography with 5 v/v % (10% conc NH4OH in MeOH) in CH2Cl2 to give 826.4 mg (92%) of the product ketone as viscous oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:37][O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([NH:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1
Reactant: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Yield: 88.6 %

Procedure:
A suspension of (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (208 mg, 0.61 mmol) in DCM (7 ml) was treated with TEA (0.14 ml, 1.0 mmol) and then with EDC (196 mg, 1.03 mmol), HOBt (140 mg, 1.03 mmol) and NH2OTHP (97 mg, 0.82 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (217 mg) as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[CH:16][N:17]=[C:13]3[NH:12][C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[CH:15]=[CH:16][N:17]=[C:13]3[N:12]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)Nc2nccn2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nccn2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
(rac)-Ethyl 5-(4-cyanophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carboxylate (152 mg, 0.49 mmol), 3-(trifluoromethyl)phenylboronic acid (187 mg, 0.1 mmol, 2 eq.), anhydrous copper(II) acetate (181 mg, 0.1 mmol, 2 eq.) and molecular sieve (200 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (5 ml), pyridine (80 μl, 0.1 mmol, 2 eq.) and triethylamine (137 μl, 0.1 mmol, 2 eq.) were added. After 12 h of stirring, more anhydrous copper(II) acetate (181 mg, 0.1 mmol, 2 eq.) and triethylamine (137 μl, 0.1 mmol, 2 eq.) were added, and the mixture was stirred for a further 48 h. The reaction was then filtered through kieselguhr, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.05% TFA). After lyophilization, the product was obtained as a solid (26 mg, 12% of theory).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:36])[N:28]([CH3:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:37](=O)[CH3:38].C=O>>[CH3:37][CH:38]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][C:27](=[O:36])[N:28]([CH3:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:24]=2)[CH2:19][CH2:18][N:17]1[S:14]([C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1)(=[O:16])=[O:15]
Reactant: CN1CCN(c2ccc(S(=O)(=O)NCCc3ccc(OC(=O)N(C)c4ccccc4)cc3)cc2)CC1
Reactant: CC=O
Agent: C=O
Product: CC1c2cc(OC(=O)N(C)c3ccccc3)ccc2CCN1S(=O)(=O)c1ccc(N2CCN(C)CC2)cc1

Procedure:
The title compound was prepared using methyl-phenyl-carbamic acid 4-{2-[4-(4-methyl-piperazin-1-yl)-benzenesulfonylamino]-ethyl}-phenyl ester as the sulfonamide and acetaldehyde in stead of formaldehyde. The crude product was purified by preparative HPLC (Gilson) (12%, brown oil).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=2)[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:27][CH:28]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: Fc1ccc(CBr)cc1
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1

Procedure:
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide was prepared from 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (Example 1) and 4-fluorobenzyl bromide by a procedure similar to that described in Example 1. Calc. for C31H38FN3O: C, 76.35; H, 7.85; N, 8.62; F, 3.90. Found C, 76.32; H, 7.86; N, 8.60; F, 3.95% 1H NMR (CDCl3, 600 MHz); δ 1.07 (d, J=6.2 Hz, 3H); 1.10 (d, J=6.3 Hz, 3H, partially overlapped by br m, 3H); 1.23 (br m, 3H); 1.93 (m, 1H); 1.98 (dd, J=11.1, 8.3 Hz, 1H); 2.54 (br m, 2H); 2.65 (m, 2H); 3.14 (d, J=13.1 Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.86 (d, J=13.1 Hz, 1H); 5.15 (s, 1H); 6.90 (t, J=8.2 Hz, 2H); 7.20 (d, J=7.3 Hz, 2H); 7.24 (m, 2H); 7.27 (m, 1H; partially overlapped by CHCl3); 7.29 (d, J=9.4 Hz, 2H); 7.33 (m, 2H); 7.46 (d, J=8.1 Hz, 2H).
Reaction SMILES: [BrH:1].[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]1([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)CCC>[Br-:2].[Br-:1].[NH2:6][CH2:5][CH2:4][CH2:3][P+:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[NH2:6][CH2:5][CH2:4][CH2:3][P+:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: NCCCBr
Reactant: Br
Solvent: CCCCO
Product: NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 120 °C
Yield: 117.3 %

Procedure:
To a stirred, degassed solution of 3-bromopropylamine hydrobromide (25.1 g, 115 mmol) in 1-butanol (210 mL) was added triphenylphosphine (42.1 g, 160 mmol). The solution was degassed again by bubbling nitrogen through it for 10 minutes and then heated at 120° C. overnight. The solution was cooled and poured into a stirring solution of methyl t-butyl ether (700 mL) and toluene (400 mL). After stirring at room temperature until a homogenous slurry resulted, the solids were filtered and the product cake rinsed two times with methyl t-butyl ether (2×100 mL) to afford the title compound (54 g, 84%), as a white solid.
Reaction SMILES: BrCCC[C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9].[CH3:16][NH:17][CH2:18][C:19]#[CH:20].C(=O)([O-])[O-].[K+].[K+].[C:27]1(C)[CH:32]=CC=C[CH:28]=1>>[CH3:16][N:17]([CH2:32][C:27]#[CH:28])[CH2:18][CH2:19][CH2:20][N:10]1[C:11](=[O:12])[C:6]2[C:7](=[CH:13][CH:14]=[CH:15][CH:5]=2)[C:8]1=[O:9]
Reactant: C#CCNC
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCN(C)CCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of bromopropylphthalimide (15.51 g, 0.058 mol), N-methyl-N-propargyl amine (5.0 g, 0.()72 mol), potassium carbonate (12.0 g, 0.087 mol), and toluene (40 ml) was refluxed for 4 hours, filtered and the insoluble washed with toluene. After removal of the solvent, the residue was dried in vacuo to provide 14.3 g of title product.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[Cl:8][C:9]1[C:10]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](F)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:8][C:9]1[C:10]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CNCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 103.8 %

Procedure:
N,N,N′-Trimethylethylenediamine (0.188 mL, 1.45 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 500 mg, 1.21 mmol) and DIPEA (0.250 mL, 1.45 mmol) in DMA (5 mL) and the mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated in vacuo to give the title compound (624 mg, 104%) as an orange solid, which was used without further purification; 1H NMR: 2.17 (6H, d), 2.89 (3H, d), 3.87-3.93 (3H, m), 6.84 (1H, s), 7.14 (1H, td), 7.31-7.38 (1H, m), 8.15 (1H, s), 8.39 (1H, d), 8.44 (1H, d), 8.69 (1H, s), 8.85 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 497.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]1([NH:19][C:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)=[S:21])[CH2:18][CH2:17]1>>[ClH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:21][C:20](=[N:19][CH:16]3[CH2:18][CH2:17]3)[N:22]2[CH:23]2[CH2:25][CH2:24]2)=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: S=C(NC1CC1)NC1CC1
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Product: Cl
Product: NS(=O)(=O)c1cc(C2(O)CSC(=NC3CC3)N2C2CC2)ccc1Cl

Procedure:
5.2 g of 2,4'-dichloro-3'-sulfamoylacetophenone and 3.1 g of 1,3-dicyclopropylthiourea were reacted according to the prescription given in Example 12 and the colorless crystalline precipitate of the end product was filtered off.
Reaction SMILES: [CH:1]1([C:4]2[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:23])[N:8]3[CH3:22])[CH2:3][CH2:2]1.Br[C:25]1[CH:26]=[C:27]([CH2:31][OH:32])[CH:28]=[N:29][CH:30]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH:1]1([C:4]2[C:12]([C:25]3[CH:30]=[N:29][CH:28]=[C:27]([CH2:31][OH:32])[CH:26]=3)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:23])[N:8]3[CH3:22])[CH2:2][CH2:3]1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2C1CC1
Reactant: OCc1cncc(Br)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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2c1ccc(-c1cncc(CO)c1)c2C1CC1
Temperature: 130 °C

Procedure:
To 4-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, (50 mg, 0.160 mmol) was added (5-bromo-pyridin-3-yl)-methanol (CAS#37669-64-0, 36 mg, 0.192 mmol), 1,2-dimethoxyethane (1.0 mL), and 2 M aqueous sodium carbonate (0.200 mL, 0.40 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (73 mg, 0.008 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 130° C. for 1 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was partially purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 10%). Further purification was accomplished via reverse phase HPLC (10 to 40% acetonitrile/water w/0.1% NH4OH) to furnish 4-Cyclopropyl-5-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 295.14485 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.17-0.25 (m, 2H), 0.72-0.80 (m, 2H), 1.87-1.98 (m, 1H), 3.25 (s, 3H), 3.64 (s, 2H), 4.83 (s, 2H), 6.80 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.80 (t, J=2.0 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: ClCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: ClCCCCCOCc1ccc(Cl)cc1
Yield: 48.3 %

Procedure:
4-Chlorobenzyl alcohol (4.3 g), 60% sodium hydride (1.8 g) and 1-bromo-5-chloropentane (6.0 g) were reacted and treated in the same manner as in Example 96 to give 3.6 g of 5-(4-chlorobenzyloxy)pentyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([O:15]C)=[CH:6][CH:5]=2.B(Br)(Br)Br.C(Cl)Cl.Cl>C(Cl)Cl>[Cl:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([OH:15])=[CH:6][CH:5]=2
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(Cl)n2Cc1ccccc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: NC(=O)Cc1c(Cl)n(Cc2ccccc2)c2ccc(O)cc12
Reaction time: 1.5 h
Yield: 103.4 %

Procedure:
A solution of 140 mg (0.43 mmol) of 2-chloro-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (Example 11) in 20 mL of methylene chloride was treated with 2 mL of 1M BBr3/CH2Cl2, stirred for 1.5 hours, stirred with aqueous HCl, the CH2Cl2 solvent separated, and washed with water, saturated NaCl solution and dried (Na2SO4). On concentrating at reduced pressure, there was obtained 140 mg of crude 2-chloro-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide. This material was dissolved in 15 mL of DMSO, 20 mg of 60% NaH/mineral oil added, and after 5 minutes, 0.1 mL of ethyl 4-bromobutyrate was added. The reaction mixture was heated by oil bath at 70° C. for 70 minutes. After cooling, the mixture was diluted with water, extracted with EtOAc, the EtOAc solution washed with water, saturated NaCl solution and dried (Na2SO4). After concentrating, a residue was obtained that was chromatographed on silca (eluted with CH2Cl2→3% MeOH/CH2Cl2) to give 105 mg of 4-[[3-(2-amino-2-oxoethyl)-2-chloro-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid ethyl ester. This ester (105 mg) was dissolved in 15 mL of EtOH, 1 mL of 5N NaOH added, and the solution stirred for 18 hours. The mixture was made acidic with 5N HCl, and extracted with EtOAc. The EtOAc solution was washed with saturated NaCl solution, dried (Na2SO4) and concentrated at reduced pressure. The residue was dissolved in MeOH/CH2Cl2, the solution concentrated, to give 75 mg (80% yield) of 4-[[3-(2-amino-2-oxoethyl)-2-chloro-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid, mp, 198-200° C.
Reaction SMILES: [C:1]([C:5]1([CH:8]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[F:9])[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[K]>COCCOCCOC>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:7][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([OH:6])[CH:8]([F:9])[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)C1(C(F)n2cncn2)CO1
Agent: [K]
Solvent: COCCOCCOC
Product: CC(C)(C)C(O)(COc1ccc(F)cc1)C(F)n1cncn1
Temperature: 0 °C
Yield: 49.1 %

Procedure:
3.0 g of 2-tert.-butyl-2-[(1H-1,2,4-triazol-1-yl)fluoromethyl]-oxirane, 1.7 g of 4-fluorophenol and 0.3 g of potassium p-fluorophenate in 10 ml of diethylene glycol dimethyl ether are stirred at 140° C. for 5 hours. After cooling, the mixture is taken up in ice water and extracted with ethyl acetate. The combined organic phases are washed with water, saturated sodium chloride solution and 2N sodium hydroxide solution and again with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystallisation from a 1:4 ether/hexane mixture gives 2.3 g of 1-(4-fluorophenoxy)-2-tert.-butyl-2-hydroxy-3-fluoro-3-(1H-1,2,4-triazol-1-yl)-propane, melting point 89°-90° C.