Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([O:26][CH2:27]C)=[O:25])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:4]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:22]=[C:21]([O:2][CH3:1])[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][N:18]=2)[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1OC
Yield: 82.4 %

Procedure:
To a methanol solution (50 ml) of 1.88 g (34.8 mmol) of sodium methoxide, a methanol solution (40 ml) of 10.1 g (28.0 mmol) of ethyl 2-(4-benzylpiperazino)-4-chloropyrimidine-5-carboxylate (the compound synthesized in Referential Example 63) was added dropwise over 10 minutes. The resultant mixture was stirred at room temperature for 1 hour. Methanol was distilled off under reduced pressure and water was added, followed by extraction with chloroform. After drying the chloroform layer with MgSO4, chloroform was distilled off under reduced pressure and the residue was recrystallized from methanol-ethyl acetate to obtain 7.9 g of the above-identified compound (yield: 79%).
Reaction SMILES: I[C:2]1[N:14]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:13][N:10]1[C:9]2=[C:4]3[CH:3]=[C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=4)[N:14]([S:15]([C:18]4[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:5]3=[N:6][CH:7]=[C:8]2[CH:12]=[N:11]1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Reactant: CS(=O)(=O)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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cccc(S(C)(=O)=O)c3)cc3c4c(cnc32)cnn4C)cc1
Temperature: 90 °C
Yield: 126.7 %

Procedure:
A mixture of 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.134 g, 0.296 mmol), 3-(methylsulfonyl)phenylboronic acid (0.711 g, 0.356 mmol, Combi-Blocks), Pd(PPh3)4 (0.24 g, 0.021 mmol, Strem), Na2CO3 (0.790 g, 0.741 mmol) in 1,4-dioxane:water (3:1, 10 mL) was heated to about 90° C. for about 5 h. The reaction mixture was filtered through a plug of Celite®. The filtrate was washed with water (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 1-methyl-7-(3-(methylsulfonyl)phenyl)-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.180 g, 0.375 mmol) that was dissolved in MeOH (3 mL) and treated with aqueous NaOH (5 N, 0.75 mL, 3.8 mmol) The reaction vessel was sealed and heated in a CEM microwave at about 120° C. for about 20 min (250 psi maximum pressure, 2 min ramp time, 300 max watts). The reaction mixture was filtered and washed with MeOH (3 mL). The filtrate was concentrated in vacuo, and purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give 1-methyl-7-(3-(methylsulfonyl)phenyl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.65 g, 53%): LC/MS (Table 2, Method d) Rt=1.23 min; MS m/z: 327 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][Zn+]>O1CCCC1.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:8][C:9]1[N:10]=[N:11][C:12]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([Cl:25])[CH:27]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(C[Zn+])c1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Clc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Temperature: 60 °C
Reaction time: 17 h
Yield: 23 %

Procedure:
To a stirred solution of 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) (1 g, 3.1 mmol) in dry tetrahydrofuran (12.2 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.153 mmol) and (3-chlorobenzyl)zinc(II) chloride (9.2 ml of a 0.5 M solution in tetrahydrofuran, 4.6 mmol). The reaction was stirred at 60° C. for 17 hours and then partitioned between ethyl acetate and water. The organic extracts were washed with water and brine and then dried, filtered and concentrated to give a yellow oil. The oil was purified using 0-70% ethyl acetate in petrol to afford the title compound (310 mg, 23%).
Reaction SMILES: [C:1](O)(=[O:4])[C:2]#[CH:3].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(C(C)C)C(C)C)C.Cl.[NH2:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][NH:43][CH2:42][C@H:41]2[OH:46])[C:33]=1[C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1>CN(C=O)C>[NH2:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][N:43]([C:1](=[O:4])[C:2]#[CH:3])[CH2:42][C@H:41]2[OH:46])[C:33]=1[C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1
Reactant: C#CC(=O)O
Reactant: Nc1ncnc(NC[C@@H]2CCNC[C@H]2O)c1-c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC(=O)N1CC[C@@H](CNc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a 20 mL reaction vial was added propiolic acid (0.02 ml; 0.37 mmol; 1.10 eq.), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (171.33 mg; 0.67 mmol; 2.00 eq.) and ethyl-diisopropyl-amine (0.28 ml; 1.68 mmol; 5.00 eq.) and 1.0 mL DMF. The reaction was stirred at rt for 1 h. Then (3S,4S)-4-{[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-piperidin-3-ol hydrochloride (144.00 mg; 0.34 mmol; 1.00 eq.) in 1.0 mL DMF was added to the reaction mixture. The reaction mixture was stirred at rt overnight and then concentrated. The crude product was subjected to preparative HPLC. Fractions containing the desired product were combined and lyophilized overnight to afford 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-yn-1-one as a white solid (35.2 mg, 18.6%). HPLC purity: 99%. MS: m/z=444 [M+H]+. 1H NMR (CD3OD) δ 8.24 (s, 1H), 7.10-7.46 (m, 9H), 4.36 (m, 2H), 4.00 (d, 1H), 3.74 (m, 1H), 3.52 (m, 1H), 3.25 (m, 1H), 3.00 (m, 1H), 2.64 (m, 1H), 1.76 (m, 2H), 1.30 (m, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Cl[C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[C:14]=1[C:15]([OH:17])=[O:16].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:25][C:18]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=2)[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1
Reactant: CCCOc1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCCOc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1

Procedure:
A mixture of 24.5 g of 4-propoxyaniline, 19.8 g of 2,6-dichloro-3-nitrobenzoic acid, and 150 ml N,N-dimethylaniline was heated under nitrogen at 100° overnight. The cooled reaction mixture was treated with dilute base and chloroform. After the aqueous layer was washed several times with chloroform, it was treated with hydrochloric acid and the resulting orange needles were collected by filtration and washed with water to give 6-chloro-3-nitro-2-[(4-propoxyphenyl)amino]benzoic acid, mp 194°-196° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH3:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CC(O[Si](C)(C)C(C)(C)C)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a 5.0 L round bottom flask containing 4-(tert-butyldimethylsilyloxy)cyclohexanone (7.03 g, 30.8 mmol) (Aldrich) was added THF (100 mL) and the reaction was cooled to −78° C. To the reaction mixture was added lithium bis(trimethylsilyl)amide (33.9 ml, 33.9 mmol) (Aldrich) and the reaction mixture was stirred for 30 minutes followed by the addition of iodomethane (2.309 ml, 36.9 mmol). The reaction mixture was stirred for 30 minutes at −78° C. and 2 hours at room temperature, quenched with saturated NH4Cl, extracted with EtOAc (200 mL), dried (NaSO4), filtered, and concentrated in vacuo. The residue was purified on SiO2 and eluted with 0-20% ethyl acetate/hexane to give a white solid (6.40 g) in 86% yield. 1H NMR (300 MHz, CDCl3) δ ppm 4.19-4.07 (m, 1H), 2.98-2.72 (m, 1H), 2.50-1.99 (m, 2H), 1.91-1.64 (m, 2H), 1.62-1.44 (m, 1H), 1.15 (dt, J=4.4, 6.8, 1H), 1.07-0.99 (m, 3H), 0.95-0.85 (m, 9H), 0.11 (d, J=1.6, 6H). MS (DCI+) M/Z 243.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.Cl.[NH2:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[OH:28][C@@H:26]([CH3:27])[CH2:25][O:24][NH:23][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (130 mg, 0.33 mmol) in THF (1.7 mL) was added (S)-1-aminooxy-propan-2-ol hydrochloride (84 mg, 0.66 mmol), DIPEA (0.23 mL, 1.32 mmol), HOBt (88 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol). After 18 hours stirring at ambient temperature, further (S)-1-aminooxy-propan-2-ol hydrochloride (84 mg, 0.66 mmol), DIPEA (0.23 mL, 1.32 mmol), HOBt (88 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) and THF (1.7 mL) were added. The reaction mixture was stirred at ambient temperature for a further 5 hours. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was then washed with methanol and the desired compound was eluted using a 2M solution of ammonia in methanol. Appropriate fractions were combined and concentrated under reduced pressure and the residue azeotroped with dichloromethane. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 10%, methanol in dichloromethane) to afford the title compound as a yellow solid (17 mg, 11%). LCMS (method A): RT=6.01 min, [M+H]+=471. 1H NMR (DMSO-d6): 8.07 (1 H, s), 7.58 (1 H, dd, J=10.71, 1.92 Hz), 7.43 (1 H, s), 7.38 (1 H, d, J=9.31 Hz), 7.31-7.28 (1 H, m), 6.89 (1 H, d, J=9.31 Hz), 6.35 (1 H, t, J=8.68 Hz), 3.69-3.60 (1 H, m), 3.45-3.38 (2 H, m), 0.96 (3 H, d, J=6.35 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br.CCN(C(C)C)C(C)C>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([N:15]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[CH:13][CH:14]=2)[O:5]1
Reactant: BrCCOCCBr
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C

Procedure:
A solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (164 mg, 0.75 mmol), 1-bromo-2-(2-bromoethoxy)ethane (418 mg, 1.8 mmol), and DIPEA (0.64 mL, 3.6 mmol) in THF (2 mL) was stirred at reflux overnight. The mixture was concentrated, diluted with water, and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography to give the title compound. MS (m/z): 290 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][OH:30].[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][O:30][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2F)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 70.5 %

Procedure:
1.02 g of p-toluensulfonyl chloride (5.35 mM), 1.24 ml of diisopropyl ethylamine (7.13 mM) and 86 mg of 4-(dimethylamino)pyridine (0.71 mM) were added to the reaction solution (3.57 mM) containing 500 mg of 2-(2-fluoro-phenyl)-ethanol (3.57 mM) dissolved in methylene chloride solution with stirring for 6 hrs at 0° C. under Ar atmosphere, and then the reaction mixture was stirred for 12 hrs at room temperature. The resulting mixture was neutralized with ammonium chloride, extracted with ethyl acetate and washed with saturated NaCl solution to separate into an organic layer and water layer. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:7) as an eluant to give 740 mg of toluen-4-sulfonate-2-(2-fluoro-phenyl)-ethyl ester (u) (yield: 70%).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][O:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].BrN1[C:19](=[O:20])[CH2:18]CC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[O-]CC.[Na+]>C(Cl)(Cl)(Cl)Cl.C(O)C>[CH2:19]([O:20][CH:12]1[C:13]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=2[O:9][CH2:10][O:11]1)[CH3:18]
Reactant: O=[N+]([O-])c1cccc2c1COCO2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC1OCOc2cccc([N+](=O)[O-])c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a stirred solution of 5-nitro4H-1,3-benzodioxine (10.0 g, 55.203 mmol) in carbon tetrachloride (70 mL) were added N-bromosuccinimide (10.808 g, 60.723 mmol) and 2,2′-azobisisobutyronitrile (0.906 g, 5.520 mmol). The mixture was stirred at 100° C. for 2 hrs. After cooled to room temperature, a solution of sodium ethoxide (4.884 g, 71.764 mmol) in ethanol (70 mL) was added to the mixture, and the stirring was continued at room temperature for 3 hrs. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=9/1) to give 4-ethoxy-5-nitro-4H-1,3-benzodioxine as a pale yellow oil (10.8 g, yield; 87%).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C@:16]12[CH2:33][CH2:32][C@H:31]3[C@@H:21]([CH2:22][CH2:23][C:24]4[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:34])[CH:25]=4)[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[C:35](O)=[O:36].C(N(CC)CC)C.FC(F)(F)S(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:35]([C@H:17]2[CH2:18][CH2:19][C@H:20]3[C@H:21]4[C@H:31]([CH2:32][CH2:33][C@:16]23[CH3:15])[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]2)[CH2:23][CH2:22]4)=[O:36])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 89 %

Procedure:
0.108 ml of benzhydrylamine was added to a solution of 100 mg of androsta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of 4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml of methylene chloride. 0.050 ml of trifluoromethanesulfonyl chloride was divided into three portions and added to this reaction mixture at intervals of 30 minutes at room temperature, whilst stirring. One hour after finishing the addition of trifluoromethanesulfonyl chloride, the reaction mixture was diluted with methylene chloride, washed with 1N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was crystallized from acetone to give 135.2 mg (yield 89%) of the title compound, having the same properties as the product of Preparation 17.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6](O)=[O:7])#[N:2].S(Cl)([Cl:15])=O>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([Cl:15])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(C(=O)O)ccc1F
Product: N#Cc1cc(C(=O)Cl)ccc1F
Temperature: 80 °C
Yield: 99.7 %

Procedure:
In a 250 mL round bottom flask a mixture of 3-cyano-4-fluorobenzoic acid (7.75 g, 0.047 mol) and thionyl chloride (28 mL, 0.38 mol, 8 eq) was heated to 80° C. for 1 h. The reaction mixture was concentrated in vacuo to give 8.6 g of 3-cyano-4-fluorobenzoyl chloride which can be used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.49-8.43 (m, 1H), 8.42-8.36 (m, 1H), 7.44 (t, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH3:17][C:18]1[C:19]([NH2:23])=[N:20][O:21][N:22]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[C:19]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[N:20][O:21][N:22]=1
Reactant: Cc1nonc1N
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nonc1NC(=O)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 30 h

Procedure:
495 mg (2.02 mmol) of 2-nitro-4-methylsulfonylbenzoic acid and 200 mg (2.02 mmol) of 4-methyl-1,2,5-oxadiazol-3-ylamine are dissolved at room temperature (RT) in 5 ml of CH2Cl2 and treated with 0.28 ml (2.02 mmol) of triethylamine, 49 mg (0.40 mmol) of 4-dimethylaminopyridine (DMAP) and 1.93 g (3.03 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 30 h at RT and subsequently washed twice with in each case 5 ml of water. The organic phase is dried over Na2SO4 and evaporated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield 350 mg (53%).
Reaction SMILES: [BH4-].[Na+].[Si:3]([N:10]1[C@@H:13]([S:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([CH:34]=[O:35])[C:11]1=[O:36])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>O1CCCC1.C(OCC)(=O)C>[Si:3]([N:10]1[C@@H:13]([S:14][C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:12]([CH2:34][OH:35])[C:11]1=[O:36])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](C=O)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CO)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a cold (ice bath) suspension of NaBH4 (227 mg, 6 mmol) in tetrahydrofuran (20 ml) was added dropwise a solution of trans 1-(t-butyldimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (2.0 g, 4.1 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature for 30 min, then diluted with ethyl acetate and washed successively with cold 1N HCl and brine. The organic layer was dried (MgSO4) and evaporated in vacuo to give the title compound (2.0 g) (quantitative) as an amorphous solid. It was used in the next step without further purification. ir νmax (CDCl3): 1740 cm-1. 1Hmr (CDCl3)δ: 7.25 (15H, m), 4.30 (1H, d, J=2, H-4), 3.28 (1H, dd, J=11, J=3, H-1'), 3.0 (1H, m, H-3), 2.55 (1H, dd, J=11, J=3, H-1'), 2.2 (1H, m, O--H), 0.9 (9H, s, t-Bu and 0.22 ppm (6H, s, CH3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]4[CH:29]=[C:30]([F:34])[C:31]([Cl:33])=[CH:32][C:26]=4[N:25]=3)=[CH:20][C:19]=2[Cl:35])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCN(CCCOC2C=CC(C=O)=CC=2Cl)CC1)=O)(C)(C)C.ClC1C=C(N)C(N)=CC=1F>>[Cl:33][C:31]1[C:30]([F:34])=[CH:29][C:27]2[NH:28][C:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:19]([Cl:35])[CH:20]=3)=[N:25][C:26]=2[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(-c3nc4cc(Cl)c(F)cc4[nH]3)cc2Cl)CC1
Agent: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C=O)cc2Cl)CC1
Agent: Nc1cc(F)c(Cl)cc1N
Product: Fc1cc2[nH]c(-c3ccc(OCCCN4CCNCC4)c(Cl)c3)nc2cc1Cl
Yield: 15 %

Procedure:
4-{3-[2-Chloro-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester. This compound was prepared by the method described in Example 1, using 4-[3-(2-chloro-4-formyl-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.6 mmol, 1.0 equiv), 4-chloro-5-fluoro-benzene-1,2-diamine (421 mg, 2.6 mmol, 1.0 equiv), and Na2S2O5 (648 mg, 3.4 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 256 mg (15%) of the title compound. MS (electrospray): mass calculated for C25H29Cl2FN4O3, 522.16; m/z found, 545.3 [M+Na]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]3[CH2:25][CH2:26][N:27]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH2:28][CH2:29]3)=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2]
Reactant: COCC(=O)Cl
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)COC)CC3)c(C)[nH]c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f17) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.