Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[NH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)=[O:46])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:50])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: C1CNCCN1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)N2CCNCC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:24]1[CH:25]=[CH:26][C:27]2[N:33]3[C:34]([CH3:37])=[N:35][N:36]=[C:32]3[C@H:31]([CH2:38][C:39]([NH:41][CH2:42][CH3:43])=[O:40])[N:30]=[C:29]([C:44]3[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=3)[C:28]=2[CH:51]=1)(=O)=O.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:50][C:47]1[CH:46]=[CH:45][C:44]([C:29]2[C:28]3[CH:51]=[C:24]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:25]=[CH:26][C:27]=3[N:33]3[C:34]([CH3:37])=[N:35][N:36]=[C:32]3[C@H:31]([CH2:38][C:39]([NH:41][CH2:42][CH3:43])=[O:40])[N:30]=2)=[CH:49][CH:48]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(OC)cc3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
4-Methoxybenzeneboronic acid (50.5 mg), sodium carbonate (64.5 mg) and bis(triphenylphosphine)palladium(II) chloride (19.4 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (150 mg) in DME (3 ml) and water (1 ml) was added and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with water (10 ml) and brine (10 ml). The organic phase was dried and the solvent was evaporated. The residue was chromatographed (0-5% methanol:DCM) to give 2-{(4S)-6-(4-chlorophenyl)-1-methyl-8-[4-(methyloxy)phenyl]-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl}-N-ethylacetamide as a light brown solid (84 mg). LCMS (formate): MH+ 500/502, RT 1.08 min
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([N:12]1CCC(=O)CC1)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>>[CH3:1][CH:2]([CH3:19])[CH:3]([NH2:12])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)C(C#Cc1ccccc1)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)C(N)C#Cc1ccccc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
A 25 ml pressure tube was charged with 1-(4-methyl-1-phenylpent-1-yn-3-yl)piperidin-4-one (76.6 mg, 0.30 mmol) and ammonium chloride (48 mg, 0.90 mmol). The pressure tube was purged with argon for 5 min and then saturated ethanolic ammonia solution (2 ml) was added. The pressure tube was sealed tightly and the reaction mixture was stirred at 90° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure and the brown residue was subjected to flash chromatography on silica gel (EtOAc/MeOH=19:1) to give 33.3 mg of a pure title compound as a yellowish oil. (yield: 64%)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
3 g of the product of Example A are refluxed for 1.5 hours in a mixture of 40 ml of glacial acetic acid, 2 ml of water and 0.6 ml of concentrated sulphuric acid. The reaction mixture is then treated with 40 ml of water and cooled to room temperature. The product is filtered off with suction, washed with water and dried. 2.08 g of the title compound are obtained (75% of theory).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.O[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:8]([N:5]1[CH2:6][CH2:7][CH:2]([O:1][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH2:3][CH2:4]1)(=[O:10])[CH3:9]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-hydroxy-piperidin-1-yl)-ethanone (1.00 g, 6.90 mmol), 4-hydroxybenzaldehyde (0.854 g, 6.90 mmol) and triphenylphosphine (1.83 g, 6.90 mmol) in THF (10 mL) was added dropwise diisopropyl azodicarboxylate (DIAD) (1.41 g, 6.90 mmol). The reaction mixture was stirred at room temperature for 16 hours, THF was evaporated, and the residue was purified by column chromatography, using dichloromethane:ethyl acetate:methanol (1:2:0.05) as eluent, to give 4-(1-acetyl-piperidin-4-yloxy)-benzaldehyde. Yield: 0.40 g (23%).
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13].[NH3:23]>C(Cl)Cl.C(O)C>[NH2:23][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13]
Reactant: N
Reactant: CCOc1ccccc1C1(Cl)C(=O)Nc2ccc(OC)cc21
Solvent: CCO
Solvent: ClCCl
Product: CCOc1ccccc1C1(N)C(=O)Nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.2 g (10 mmol) of the intermediate from step B were suspended in 40 ml CH2Cl2. 50 ml of a 2M solution of NH3 in ethanol were added and the reaction mixture was stirred for 16 h at ambient temperature. The mixture was poured into an ice/water mixture and the precipitate was separated. The precipitate was redissolved in ethyl acetate. This organic phase was washed with 2M aqueous HCl. The aqueous phase was made alkaline (pH=8-9) and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to yield 1.7 g of the intermediate.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@:19]12(O)[N:26](C)[C@@H:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]=[CH:20]2.[Na].O>C(#N)C>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][C@@:11]23[N:26]([CH3:19])[C@@H:23]([CH2:24][CH2:25]2)[CH2:22][CH:21]=[CH:20]3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(C)(c1ccccc1)c1ccccc1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(C)(c1ccccc1)c1ccccc1)CC2

Procedure:
4.80 g (0.02 mol) of methyl 2,2-diphenylpropionate 3b, 2.78 g (0.02 mol) of tropenol, and 0.046 g of sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water, shaking from time to time. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4, and evaporated to dryness. From the residue, 4c is precipitated as the hydrochloride and this is recrystallized from acetone. Yield: 5.13 g (67% of theory); TLC: Rf value: 0.28 (eluent: sec-butanol/formic acid/water 75:15:10); melting point: 134° C.-135° C.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([C:12](O)=[O:13])=[CH:8][C:7]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:6]1=2)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([C:12]([Cl:23])=[O:13])=[CH:8][C:7]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c2c(cc(C(=O)O)c1=O)CCCCCC2
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCn1c2c(cc(C(=O)Cl)c1=O)CCCCCC2

Procedure:
1-Butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carboxylic acid (B-01) (416 mg, 1.50 mmol) was dissolved in toluene (15 ml), and to the reaction mixture was added thionyl chloride (328 μL, 4.50 mmol), and the reaction mixture was reacted at 65° C. for 20 min. The reaction mixture was evaporated under reduced pressure to give 1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carbonyl chloride (B-02).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[CH:9]=[C:8]3[NH:11][C:12]([NH:14][CH3:15])=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.O>N1C=CC=CC=1>[CH3:22][C:2]1([CH3:1])[C:10]2[CH:9]=[C:8]3[N:11]([S:30]([C:27]4[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=4)(=[O:32])=[O:31])[C:12]([NH:14][CH3:15])=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC)nc3cc21
Solvent: c1ccncc1
Solvent: O
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(NC)n3S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.8 %

Procedure:
To a solution of 7,7-dimethyl-2-methylamino-5-pentyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (230 mg) in pyridine (6 ml) is added 4-methyl-benzenesulfonyl chloride (160 mg; 0.84 mmol) at 0° C. After addition the mixture is warmed to RT and stirred for 48 h. The reaction solution is dissolved with water and the aqueous layer is extracted with EtOAc. The combined organic layer is washed with hydrochloric acid (0.5 N) and brine, dried over Na2SO4 and concentrated in vacuo. The compound (135 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (40:1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:39]=[CH:40][CH:41]=1)[C:15]([NH:17][CH2:18][C:19]1[C:20]([NH:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:21]2[CH:29]=[N:28][N:27]([CH2:30][CH3:31])[C:22]2=[N:23][C:24]=1[CH2:25][CH3:26])=[O:16])=[O:10].[CH3:42][NH:43][CH2:44][CH2:45][OH:46].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:30]([N:27]1[C:22]2=[N:23][C:24]([CH2:25][CH3:26])=[C:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]3[CH:39]=[CH:40][CH:41]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]([CH2:44][CH2:45][OH:46])[CH3:42])[CH:13]=3)[C:20]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:21]2[CH:29]=[N:28]1)[CH3:31]
Reactant: CNCCO
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(NC(=O)CCCCCCCBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(NC(=O)CCCCCCCN(C)CCO)c1
Temperature: 60 °C

Procedure:
A solution of 3-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (42 mg, 0.067 mmol, e.g. which can be as prepared in Intermediate 47) in N,N-dimethylformamide (3 ml) was treated with 2-(methylamino)ethanol (0.011 ml, 0.13 mmol, commercially available e.g. from Aldrich) and N,N-diisopropylethylamine (0.0235 ml, 0.13 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (33 mg). LCMS showed MH+=622; TRET=2.21 min.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].ClC1N=C2SC(C(NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=O)=CC2=NC=1.NC[CH2:72][N:73]([CH3:75])[CH3:74]>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH2:30][CH2:72][N:73]([CH3:75])[CH3:74])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Reactant: CN(C)CCN
Agent: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(NCCN(C)C)nc2s1
Yield: 36 %

Procedure:
Preparation analogous to 96a by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.061 mmol, 30 mg) and 1-amino-2-dimethylaminoethane (1.531 mmol, 167 μL, 135 mg) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(2-(dimethylamino)ethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96c (12 mg, 36%). NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.22 (s, 6H), 2.24 (s, 3H), 3.45 (q, J=5.9 Hz, 2H), 7.28 (d, J=8.2 Hz, 1H), 7.61 (m, 2H), 7.75 (m, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.95 (d, J=7.4 Hz, 1H), 8.05 (s, 1H), 8.19 (s, 1H), 8.24 (s, 1H), 10.07 (s, 1H), 10.33 (s, 1H). (m/z)=542 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[CH2:10](Br)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:11][CH2:10][CH:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH3:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCc1ccccc1
Reactant: CCc1ccncc1C
Product: Cc1cnccc1C(C)CCc1ccccc1
Yield: 64.6 %

Procedure:
1.13 g (9.35 mmol) of 3-methyl-4-ethylpyridine and 1.73 g (9.35 mmol) of phenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.36 g of the desired compound (yield: 64.5%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:14])[N:3]=1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccccc2n1
Reaction time: 4 h

Procedure:
To a solution of ethyl 4-chloroquinazoline-2-carboxylate (0.6 g, 2.53 mmol) in THF (6 mL) at −40° C., was added dropwise a 1 M solution of 4-fluorophenylmagnesium bromide in THF (3 mL, 3.0 mmol, 1.2 eq). The mixture was stirred at −40 C for 4 h. The reaction was quenched by adding 0.5 N HCl solution (5 mL) and the mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine and dried over MgSO4. The crude product was purified on a silica gel column using a mixture of EtOAc-hexanes as eluent. (4-chloroquinazoline-2-yl)(4-fluorophenyl)methanone was obtained as a light yellow solid (440 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ 7.45-740 (m, 2H), 8.07-8.03 (m, 1H), 8.17-8.13 (m, 2H), 8.23 (m, 2H), 8.42 (d, 1H); LC-MS (ESI) m/z 287 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:22]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1>>[C:4]([Si:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)[CH2:11][I:22])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)OCC(CO)COc1ccc(I)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)OCC(CI)COc1ccc(I)cc1
Yield: 94 %

Procedure:
Iodination of alcohol 169 with I2, PPh3 and imidazole as in Example 2GGG above for 12 h, followed by chromatography of the product on silica gel, eluting with 0-5% CH2Cl2/petroleum ether (foreruns) and then with 5-10% CH2Cl2/petroleum ether, gave tert-butyl {3-iodo-2-[(4-iodophenoxy)methyl]propoxy}dimethylsilane (171) (94%) as a colourless oil; 1H NMR (CDCl3) δ 7.55 (dt, J=9.0, 2.7 Hz, 2H), 6.68 (dt, J=9.0, 2.7 Hz, 2H), 3.98 (dd, J=9.4, 5.7 Hz, 1H), 3.92 (dd, J=9.4, 6.2 Hz, 1H), 3.74 (dd, J=10.1, 5.6 Hz, 1H), 3.69 (dd, J=10.1, 5.6 Hz, 1H), 3.38 (dd, J=10.0, 5.9 Hz, 1H), 3.35 (dd, J=10.0, 6.1 Hz, 1H), 2.09 (sept, J=5.8 Hz, 1H), 0.89 (s, 9H), 0.06 (2 s, 6H); HRFABMS calcd for C16H27I2O2Si m/z [M+H]+ 532.9870. found 532 9864.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([OH:19])[C:14]([OH:18])=[CH:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:27](Br)[C:28]([OH:30])=[O:29]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]3[O:18][CH:27]([C:28]([OH:30])=[O:29])[O:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccc(Br)cc1
Reactant: O=C(O)C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1S(=O)(=O)c1ccc(Br)cc1)OC(C(=O)O)O2

Procedure:
In a manner analogous to that described in Example 15, 60.0 g of 4-(4-bromophenylsulphonyl)-5-methyl-1,2-benzenediol are reacted in the presence of 120 g of potassium carbonate in 300 ml of dimethylformamide with a solution of 76.2 g of dibromoacetic acid in 100 ml of dimethylformamide. After working up and chromatographic purification in a manner analogous to that described in Example 15 and crystallisation from 1,2-dichloroethane, 5-(4-bromophenylsulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained in the form of sand-coloured crystals having a melting point of 170°-172.5°.
Reaction SMILES: C(OC([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH:13]=[C:12]1[CH2:24][CH2:25][CH3:26])=O)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:24]([C:12]1[NH:11][C:19]2[C:14]([CH:13]=1)=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH2:25][CH3:26]
Reactant: CCCc1cc2ccc(C(=O)OC)cc2n1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
To a solution of methyl 1-benzyloxycarbonyl-2-propylindole-6-carboxylate (200 mg) in a mixture of methanol and ethyl acetate (1:1, 8 ml) was added 10% palladium on carbon (30 mg), and the mixture was stirred under hydrogen atmosphere or 20 minutes. The catalyst was removed by filtration through celite and washed with methanol. The filtrate was evaporated in vacuo to give methyl 2-propylindole-6-carboxylate (112 mg) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([F:12])[CH:4]=1.CCN(C(C)C)C(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1COCC1>[F:12][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=1)[CH2:2][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)cc(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A −20° C. solution of 1-(bromomethyl)-3-fluoro-5-nitrobenzene (0.95 g, 4.06 mmol) and DIEA (1.418 ml, 8.12 mmol) in THF (20 mL) was treated drop-wise with a solution of 1-methylpiperazine (0.488 g, 4.87 mmol) in THF (10 mL) and stirred at RT overnight as the cooling bath expired. The solid was removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 1-(3-fluoro-5-nitrobenzyl)-4-methylpiperazine (820 mg, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.97 (dt, J=8.6, 2.3 Hz, 1H), 7.64 (dd, J=9.2, 2.2 Hz, 1H), 3.60 (s, 2H), 2.41 (s, 8H), 2.21 (s, 3H); MS (ESI) m/z: 254.1 [M+H]+.
Reaction SMILES: [N+:1]([O:4][C@@H:5]([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([O-:3])=[O:2].[C:17](Cl)(=O)[C:18]([Cl:20])=O.C(=O)C>CN(C)C=O.ClCCl.[Cl-].[Zn+2].[Cl-]>[N+:1]([O:4][C@@H:5]([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH:18]([Cl:20])[CH3:17])=[O:10])([O-:3])=[O:2]
Reactant: O=C(O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: CC=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cl)OC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dichloromethane (10 mL) solution of (5R)-5,6-bis(nitrooxy)hexanoic acid (292 mg, 1.22 mmol) was added oxalyl chloride (0.54 mL, 6.12 mmol), followed by a few drops of N,N-dimethylformamide. After bubbling has stopped, the reaction mixture was concentrated in vacuo to afford a yellow slurry, which was redissolved in dichloromethane (5 mL). This solution was added to a mixture of zinc chloride (166 mg, 1.22 mmol) and acetaldehyde (0.15 mL, 2.66 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture turned cloudy immediately. It was warmed up to room temperature, stirred for 1 hour, and concentrated in vacuo to afford the crude product. Chromatography over silica eluting with ethyl acetate/hexanes afforded the diastereomeric 1-chloroethyl (5R)-5,6-bis(nitrooxy)hexanoate as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 6.54 (q, J=5.8 Hz, 1H, D1), 6.54 (q, J=5.8 Hz, 1H, D2), 5.25-5.35 (m, 1H), 4.76 (dd, J=3.1, 13.0 Hz, 1H, D1), 4.76 (dd, J=3.0, 12.8 Hz, 1H, D2), 4.49 (dd, J=6.5, 12.9 Hz, 1H, D1), 4.49 (dd, J=6.4, 13.1 Hz, 1H, D2), 2.4-2.5 (m, 2H), 1.7-1.9 (m, 7H).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]2[CH2:6][NH:7][CH2:8][CH:2]12.I[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][C:23]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)(=[O:29])=[O:28])=[CH:22]2>>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([S:27]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[N:7]2[CH2:6][CH:3]3[CH:2]([N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:8]2)(=[O:29])=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC21
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cnc2c(I)cccc2c1
Product: CC(C)(C)OC(=O)N1CCC2CN(c3cccc4cc(S(=O)(=O)c5cccc(C(F)(F)F)c5)cnc34)CC21
Yield: 56 %

Procedure:
The title compound was prepared by analogy to the procedure of Example 1.3, except using tert-butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate and 8-iodo-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline. 133 mg (56%) of the title compound were obtained as a pale yellow solid.