Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=C(CCC[N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])C=CC=1.C(Br)CCCC>>[C:12]1(=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[NH:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Solvent: CCCCCBr
Product: O=C1NC(=O)c2ccccc21

Procedure:
Alkylation reaction of phenol 58 with pentyl bromide gave 24343-(pentyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.549 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.81-7.84 (m, 2H), 7.69-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.73 (s, 1H), 6.66 (dd, J=7.8, 2.2 Hz, 1H), 3.91 (t, J=6.8 Hz, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.01-2.07 (m, 2H), 1.73-1.78 (m, 2H), 1.34-1.48 (m, 4H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C(OC(C)(C)C)=O)[CH:14]=[C:13]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:27]=2)=[N:7][N:6]=1)(=O)=O.[OH-:38].[Na+].Cl>>[O:35]1[CH2:34][CH2:33][N:32]([C:28]2[N:27]=[C:26]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:8]5[S:9][C:5]([OH:38])=[N:6][N:7]=5)[CH:11]=4)[NH:15][CH:14]=3)[CH:31]=[CH:30][CH:29]=2)[CH2:37][CH2:36]1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Agent: Cl
Agent: [Na+]
Product: Oc1nnc(-c2ccc3[nH]cc(-c4cccc(N5CCOCC5)n4)c3c2)s1
Temperature: 120 °C
Yield: 14.2 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (160.0 mg, 0.296 mmol) and aq. 10 M NaOH (1.5 mL, 15.0 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min. The mixture was neutralized with aq. 5 N HCl and the mixture was extracted with CHCl3/iPrOH (4:1). The combined organic layers were dried, filtered and concentrated. The crude product was dissolved in MeOH/p-dioxane (2:1, 3 mL) and catalytic amount of Pd/C was added. The mixture was stirred under H2 for 2 h, then filtered through a plug of celite. The filtrate was concentrated and the residue was purified with RP-HPLC to give 5-(3-(6-morpholinopyridin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-ol (16.0 mg, 0.042 mmol, 14%) as a pink solid. MS (ESI, pos. ion) m/z 380 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.87 (1H, br. s.), 11.71 (1H, br. s.), 8.83 (1H, s), 8.12 (1H, d, J=2.5 Hz), 7.46-7.63 (3H, m), 7.20 (1H, d, J=7.6 Hz), 6.63 (1H, d, J=8.2 Hz), 3.76-3.87 (4H, m), 3.53-3.65 (4H, m).
Reaction SMILES: [CH3:1][Mg]Br.[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[NH4+].[Cl-]>C(OCC)C>[OH:4][C:5]1([CH3:1])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3M methyl magnesium bromide in diethyl ether (2.0 mL) in diethyl ether (3 mL) at 0° C. was treated with a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.0 g, 5.00 mmol) in diethyl ether (5 mL), warmed to room temperature, stirred for 18 hours, treated with saturated NH4Cl, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentratet was purified by flash chromatography on silica gel with 20%-50% ethyl acetate/heptane to provide the desired product. MS (DCI(+)) m/e 216 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C@H:9]2[CH2:13][C@H:12]([OH:14])[C@H:11]([CH2:15][OH:16])[CH2:10]2)[CH:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C@@H:24]([NH2:28])[C@@H:23]([O:29][CH3:30])[CH2:22]2.C(N(CC)C(C)C)(C)C.C(Cl)Cl>CN1CCCC1=O>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C@@H:24]([NH:28][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C@H:9]3[CH2:13][C@H:12]([OH:14])[C@H:11]([CH2:15][OH:16])[CH2:10]3)[CH:3]=1)[C@@H:23]([O:29][CH3:30])[CH2:22]2
Reactant: OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O
Reactant: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O)C2)ncn1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
To a 500 ml Parr pressure vessel was added (1S,2S,4R)-4-(6-chloropyrimidin-4-yloxy)-2-(hydroxymethyl)cyclopentanol (26) (25.00 g, 102.2 mmol) in N-methylpyrrolidinone (200 mL). To this mixture was added (1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (31.10 g, 132.8 mmol) followed by N,N-diisopropylethylamine (88.99 mL, 510.9 mmol). The vessel was then sealed, pressurised with 30 psi of nitrogen and heated to 130° C. for 22 hours. The pressure increased to 50 psi when the reaction reached temperature and held during the course of the reaction. After 22 hours the reaction was cooled to ambient temperature and the pressure was vented. Methylene chloride (250 mL) was added to the reaction mixture and this was then extracted with saturated sodium bicarbonate in water (250 mL). The organic layer was then extracted four times with water (250 mL) and once with saturated sodium chloride in water (250 mL). The organic layer was then dried over sodium sulfate (7.5 g), filtered and concentrated. To the black semisolid oil was added acetonitrile (250 mL) and the mixture was stirred for 2 hours at ambient temperature. During this time a beige solid precipitated and was filtered and dried under reduced pressure at 40° C. for 16 hours. A light biege solid was afforded (17 g, 41%). 1H NMR (300 MHz, CD3OD, δ): 8.19 (s, 1H), 7.25 (s, 1H), 7.18 (m, 2H), 5.97 (s, 1H), 5.58 (m, 1H), 5.30 (m, 1H), 4.41 (m, 1H), 4.22 (m, 1H), 3.76 (m, 1H), 3.61 (m, 1H), 3.30 (s, 3H), 3.05 (m, 2H), 2.30 (m, 2H) and 1.97 (m, 3H).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([CH2:8][C:9]([S:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17](=[N:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[CH3:18])[CH2:13]2)=[O:10])[N:6]([C:33]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])=[C:34]([CH3:36])[CH3:35])[C:5]1=[O:50])[CH3:3].[N+:51]([C:54]1[CH:64]=[CH:63][C:57]([CH2:58][O:59][C:60](Cl)=[O:61])=[CH:56][CH:55]=1)([O-:53])=[O:52]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:20]([N:19]=[C:17]([N:14]2[CH2:15][CH2:16][C@H:12]([S:11][C:9]([CH2:8][C@H:7]3[N:6]([C:33]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=4)=[O:38])=[C:34]([CH3:35])[CH3:36])[C:5](=[O:50])[C@@H:4]3[C@H:2]([O:1][C:60]([O:59][CH2:58][C:57]3[CH:56]=[CH:55][C:54]([N+:51]([O-:53])=[O:52])=[CH:64][CH:63]=3)=[O:61])[CH3:3])=[O:10])[CH2:13]2)[CH3:18])=[O:21])=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(C)C)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(C)C)C1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
56 mg (0.079 mmole) of (3S, 4R)-3-[(R)-1-hydroxyethyl]-4-([(S)-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl)-1-[2-methyl-1-(p-nitrobenzyloxycarbonyl)prop-1-enyl]-2-azetidinone were dissolved in 1.5 ml of methylene chloride. To the solution were added, in turn, 29 mg (0.24 mmole) of 4-(N,N-dimethylamino)pyridine and 51 mg (0.24 mmole) of p-nitrobenzyloxycarbonyl chloride, with stirring at 0° C. The reaction mixture was stirred at room temperature for 3 hours, diluted with methylene chloride, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent was distilled off and the residue was subjected to thin layer chromatography using silica gel, developed with a 1:5 by volume mixture of hexane and ethyl acetate, to afford 30 mg (yield 42%) of the title product as an oily substance. 8 mg (14%) of the starting material was also recovered.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[CH:7][C:8]([CH3:18])=[C:9]([C:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2].[CH3:22][NH:23][CH3:24].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[CH:1]([O:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[CH:7][C:8]([CH3:18])=[C:9]([C:11]2[CH2:16][CH2:15][CH:14]([N:23]([CH3:24])[CH3:22])[CH2:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCC(=O)CC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCC(N(C)C)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 4-(5-isopropoxy-2-methyl-4-nitrophenyl)cyclohex-3-enone (0.1 mmol) and dimethylamine (0.11 mmol) in 2 mL of 1,2-dicholoroethane, is added AcOH (0.1 mmol) and NaBH(OAc)3 (0.11 mmol). The reaction mixture is stirred at room temperature for 10 hours. After workup and silica flash chromatography (CH2Cl2/MeOH 9:1), 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-N,N-dimethylcyclohex-3-enamine is obtained. MS (ES+): 319.19 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][CH2:13][CH2:14][CH2:15][C:16](=[O:17])[O:18][CH2:19][CH3:20]
Reactant: COC(=O)c1ccccc1N
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCNc1ccccc1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of 19.2 g of methyl 2-aminobenzoate and 9.6 g of ethyl γ-bromobutyrate is heated at 80°-85° C. for 24 hours, cooled to room temperature and filtered. The solid is washed with CH2Cl2 and the filtrate washed with 1NHCl, H2O, 1NNaHCO3 and brine. The solvent is removed to give an oil. The oil is distilled and the fraction boiling at 45°-75° C. and 130°-160° C. were collected and discarded. The residue is the product (55.4 g of oil)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=O)C1C=CC=CC=1.C[Si](I)(C)C.CO>C(Cl)(Cl)Cl>[C:22]1([C:19]2[O:18][C:17]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][NH:11]3)=[N:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)N1CCCCC1c1ncc(-c2ccccc2)o1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc(-c2cnc(C3CCCCN3)o2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.7 %

Procedure:
To a solution of 0.56 g (1.5 mmol) of 2-(5-Phenyl-oxazol-2-yl)-piperidine-1-carboxylic acid benzyl ester in 5 mL of chloroform, cooled in an ice bath under argon, was added 5 mL of trimethylsilyliodide. The mixture was allowed to slowly warm to room temperature and stir for five hours. To the reaction mixture was added 10 mL of methanol and the resulting mixture was allowed to stir at room temperature for 0.5 hour. The resulting mixture was partitioned between diethyl ether and 2N hydrochloric acid. The aqueous layer was separated, basified with 2N sodium hydroxide and extracted twice with diethyl ether. The combined ethyl ether extracts were dried over magnesium sulfate and concentrated to 0.20 g (0.88 mmol, 58% yield) of a yellow oil. The oil was 98% pure by LC analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].I[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1>O.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccc(I)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(Sc2ccc(Cl)cc2)cc1

Procedure:
A solution of 6.0 g of 4-chlorothiophenol and 8.0 g of potassium hydroxide in 80 ml of water is heated to 50° C. and 0.8 g of copper powder and 10.4 g of 4-iodophenylacetic acid are added. The mixture is heated to reflux and maintained at reflux overnight. The mixture is then cooled and filtered. The filtrate is acidified with concentrated HCl to give a white solid which, on recrystallization from methanol, yields cream colored plates, mp 135°-140° C. A sample is recrystallized from chloroform-hexane to give white plates, mp 144.5°-148° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([O:39]CC)=[O:38])=[CH:33][CH:32]=4)=[CH:27][CH:26]=2)[CH:19]=[CH:18]3)=[O:14])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([OH:39])=[O:38])=[CH:35][CH:36]=4)=[CH:27][CH:26]=2)[CH:19]=[CH:18]3)=[O:14])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(Cn3ccc4cc(C(=O)N[C@@H](C)c5ccc([N+](=O)[O-])cc5)ccc43)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(-c3ccc(C(=O)O)cc3)cc2)c1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of (S)-ethyl 4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate (23 mg, 0.04 mmol, 1 equiv) in MeOH (1 mL) was added 100 L of a 5 N NaOH solution. The mixture is stirred at room temperature overnight and then hydrolyzed by addition of a 1 N HCl solution. After concentration, the crude is purified by preparative HPLC to afford a beige powder (9 mg, 0.02 mmol, 43%). ESI-MS (m/z): 520 [M+H]+.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>CN(C=O)C>[CH:33]1([C:36]([N:21]2[CH2:20][CH2:19][C:17]3[N:18]=[C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([C:5]5[O:1][CH:2]=[N:3][CH:4]=5)=[CH:7][CH:8]=4)[N:14]=[C:15]([N:23]([CH2:24][CH2:25][OH:26])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:16]=3[CH2:22]2)=[O:37])[CH2:35][CH2:34]1
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: O=C(Cl)C1CC1
Solvent: CN(C)C=O
Product: O=C(C1CC1)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (50 mg, 0.12 mmol, Example 1) was dissolved in DMF (3 mL). Cyclopropanecarbonyl chloride (10.59 μL, 0.12 mmol) was added and the reaction was stirred at room temperature for 4 h. An extra equivalent of cyclopropanecarbonyl chloride was added and the reaction was stirred for 2 h. The solvent was evaporated, the crude dissolved in few drops dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding cyclopropyl(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone (1.8 mg, 2.96%).
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([Mg]Br)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[Cl:1][CH:2]([CH3:6])[C:3](=[O:4])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: CC(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(Cl)C(=O)CCc1ccccc1

Procedure:
In two multi-injection microreactors having 4 reaction regions (each comprising one injection point, one mixing zone and one reaction zone of 1.08 mL internal reaction volume), 2-chloro propionic chloride (13.5 wt %) in tetrahydrofuran (THF, 86.5 wt %) as flow A and phenethyl-magnesium bromide (1 eq., 10 wt %) in THF (1 eq., 90 wt %) as flow B were reacted. Micro-reactor MR1 comprised internal heat exchange structures and provided a very efficient cooling (VEC) while temperature adjustment of metal microreactor MR2 was performed by submersing the microreactor in a temperature adjusted bath and provided only a low efficient cooling (LEC) between the injection points. The temperatures were displayed in table 3. Total flow rates of 20 and 40 g/min after last injection were performed. The 2nd reactant (flow B) is fed to the first reactant in a proportion corresponding to the number of inlet points. About 25 mol-% of flow B necessary to reach completion of the reaction respectively were fed at each inlet point to the first flow. After the last injection the reagents of flow B and flow A were fed in equimolar amount. The yields of the product 4-chloro-1-phenyl-pentan-3-one being collected after the respective reaction zone and quenched are shown in table 2 in relation to feed rate and cooling conditions.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([OH:54])=O)=[CH:40][CH:41]=2)[N:36]=1.Cl.[CH2:56]1[C:65]2[C:60](=[C:61]([O:66][CH2:67][C:68]3[CH:69]=[C:70]([CH:73]=[CH:74][CH:75]=3)[C:71]#[N:72])[CH:62]=[CH:63][CH:64]=2)[CH2:59][CH2:58][NH:57]1>CN(C)C=O>[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([N:57]3[CH2:58][CH2:59][C:60]4[C:65](=[CH:64][CH:63]=[CH:62][C:61]=4[O:66][CH2:67][C:68]4[CH:69]=[C:70]([CH:73]=[CH:74][CH:75]=4)[C:71]#[N:72])[CH2:56]3)=[O:54])=[CH:40][CH:41]=2)[N:36]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: N#Cc1cccc(COc2cccc3c2CCNC3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(N)nc3cc(C(=O)N4CCc5c(cccc5OCc5cccc(C#N)c5)C4)ccc23)CC1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 uL, 0.07 mmol) were added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) and 3-[(1,2,3,4-tetrahydroisoquinolin-5-yloxy)methyl]benzonitrile HCl salt (30 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) at r.t. The reaction was stirred for 2 h. and the product was purified without workup by RP-HPLC (pH=10) to afford the desired compound (0.015 g, 33%) as an amorphous white solid. 1H NMR (500 MHz, DMSO): δ 7.79 (s, 1H), 7.71 (m, 2H.), 7.67 (d, 1H), 7.52 (t, 1H), 7.20 (s, 1), 7.05 (t, 1H), 6.96 (d, 1H), 6.83 (d, 1H), 6.70 (bs, 1H.), 6.02 (s, 2H.), 5.10 (s, 2H), 4.61 (m, 2H), 3.54 (m, 4H), 2.96 (s, 4H), 2.74 (m, 2H.), 2.44 (m, 2H.), 2.18 (s, 3H). (NMR sample heated to 90 c); Analytical LCMS (M+H)+: m/z=534.1.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:20][C@@H:21]1[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:13]([NH:20][C@@H:21]1[CH2:25][CH2:24][C@H:23]([CH2:26][O:27][N:29]2[C:33](=[O:34])[C:32]3[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]2=[O:39])[CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CON2C(=O)c3ccccc3C2=O)C1

Procedure:
A solution of 2.94 ml (0.01755 mol) of diethyl azodicarboxylate (93%) in 10 ml of benzene is added dropwise to a mixture of 3.6 g (0.01672 mol) of cis-3-(N-BOC-amino)-cyclopentanemethanol, 2.73 g (0.01673 mol) of N-hydroxyphthalimide, 4.49 g (0.01672 mol) of triphenylphosphine and 60 ml of benzene at 20°-30° C., while stirring. After the mixture has been stirred at room temperature for 1 hour, the precipitate formed during the reaction is filtered off, the residue on the filter is suspended in benzene and the suspension is filtered again. The latter operation is repeated twice more (residue on the filter: diethyl 1,2-hydrazinedicarboxylate), and the resulting filtrates are combined and these are evaporated in vacuo. Purification of the residue is carried out by means of flash chromatography on silica gel using ethyl acetate/hexane mixtures (1:3 and 1:1). The title compound is thus obtained, m.p. 162°-163° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=1.Cl.C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>C1COCC1>[Cl:14][C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=3)[CH:17]=[CH:16][CH:15]=2)[C:12]([Cl:13])=[CH:11][N:10]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1cccc(CNc2nc(Cl)ncc2Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(CNc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of N-(3-aminobenzyl)-2,5-dichloropyrimidin-4-amine.hydrogen chloride (0.10 g, 0.29 mmol) (prepared according to Example 3, step B) and triethylamine (0.16 mL, 1.2 mmol) in THF (3 mL) was added slowly 3-nitrobenzoyl chloride (54 mg, 0.29 mmol). The resulting mixture was stirred at rt for 2 hours and concentrated under vacuum. The residue was partitioned in EtOAc and water. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give the desired product as a yellow solid (90 mg, 70%). LCMS for C18H14Cl2N5O3 (M+H)+: m/z=418.0, 420.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(O)=O)=[C:5]2[CH3:14].[H-].[Na+].[CH3:17][C@@H:18]1[CH2:20][O:19]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C@H:18]([OH:19])[CH3:20])[CH:6]=[C:5]2[CH3:14]
Reactant: Cc1c(C(=O)O)[nH]c2ccc(F)cc12
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cn(C[C@@H](C)O)c2ccc(F)cc12
Reaction time: 5 h
Yield: 70 %

Procedure:
A suspension of 1.16 g of 5-fluoro-3-methyl-indole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 5 hours and, after cooling to 0°, diluted with 30 ml of tetrahydrofuran. 225 mg of sodium hydride dispersion were added and the mixture was stirred for one hour. Subsequently, 0.63 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 90 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium surfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with hexane-toluene (1:1) and subsequently with toluene-ethyl acetate (19:1). 0.87 g (70%) of (R)-1-(5-fluoro-3-methylindol-1-yl)-propan-2-ol was obtained as a pale brown oil.