Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1[N:31]=[C:32]([SH:35])[NH:33][CH:34]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1[N:31]=[C:32]([S:35][C:2]2[S:6][C:5]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[O:9])=[N:4][CH:3]=2)[NH:33][CH:34]=1)=[O:29])[CH3:26]
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: CCOC(=O)c1c[nH]c(S)n1
Product: CCOC(=O)c1c[nH]c(Sc2cnc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)s2)n1
Yield: 38 %

Procedure:
2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-1H-imidazole-4-carboxylic acid ethyl ester (190 mg, 38%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-mercapto-1H-imidazole-4-carboxylic acid ethyl ester (340 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH2:12][C:13]2[CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[N:16]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)[N:4]=1.[OH-].[Na+]>C(O)C.O>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH2:12][C:13]2[CH:14]=[C:15]([C:25]([OH:27])=[O:26])[N:16]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)[N:4]=1
Reactant: COC(=O)c1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 610 mg (1.34 mmol) of methyl 5-(3,5-bistrifluoromethylpyrazol-1-ylmethyl)-2-(3-chloropyridin-2-yl)-2H-pyrazole-3-carboxylate in 9 ml of ethanol is admixed dropwise with a solution of 699 mg (1.78 mmol) of sodium hydroxide in 7 ml of water. The mixture is stirred at room temperature for 2 hours and concentrated to about 5 ml on a rotary evaporator. This residue is admixed with 5 ml of tert-butyl methyl ether and the organic phase is subsequently washed with water. The combined aqueous phases are adjusted to a pH of about 3 with concentrated hydrochloric acid, with ice cooling, and are extracted with three times 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and then the solvent is removed on a rotary evaporator.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10](Cl)=[O:11].[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10]([NH:21][CH2:20][CH2:19][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:11]
Reactant: NCCN1CCOCC1
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc([N+](=O)[O-])cc1C(=O)NCCN1CCOCC1
Reaction time: 8 h
Yield: 87.9 %

Procedure:
1-Methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (0.585 g, 4.70 mmol; see step (ii) above) in DCM (10 mL), was added dropwise to a solution of 2-(4-morpholinyl)ethanamine (0.673 g, 5.17 mmol), and NEt3 (0.735 μL, 9.42 mmol), in DCM (10 mL) over 15 min. The resulting solution was allowed to stir overnight and the reaction quenched with a 5% NaOH solution (20 mL). The layers were separated and the DCM fraction collected, dried (MgSO4), filtered and the solvent removed under reduced pressure to yield the sub-title compound as a white/pale yellow solid (1.166 g, 88%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]3[N:13]([N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]=3[C:17]([NH2:19])=[O:18])[C:7]=2[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].O1CCOCC1.[ClH:39]>>[Cl:39][CH2:3][CH2:2][C:1]([N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]3[N:13]([N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]=3[C:17]([NH2:19])=[O:18])[C:7]=2[CH2:6]1)=[O:4]
Reactant: C=CC(=O)N1CCc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1
Reactant: Cl
Solvent: C1COCCO1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CCN(C(=O)CCCl)C3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
7-Acryloyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide (40 mg, 0.09 mmol) was suspended in Sat. HCl (gas)/dioxane (50 mL), then the mixture was stirred RT for about 1.5 hr, and concentrated to dryness. The residue was suspended into 2 mL of MeOH and 2 mL of water. The organic layer was discarded, aqueous layer was lyophilized to get 40 mg (90%) of 7-(3-chloropropanoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.79-11.76 (m, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.43 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.10-7.04 (m, 4H), 4.71-4.70 (m, 2H), 3.85-3.79 (m, 4H), 3.02 (t, J=6.4 Hz, 2H), 2.79-2.69 (m, 2H). MS (ESI) m/e [M+1]+ 463.8, 465.8.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[CH:5][N:6]=1.[C:16]([Si:20]([CH3:41])([CH3:40])[O:21][CH:22]1[C:30]2[C:25](=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([CH3:19])([CH3:18])[CH3:17].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>[Si:20]([O:21][CH:22]1[C:30]2[C:25](=[C:26]([C:2]3[S:3][C:4]([C:7]4[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=4)[C:12]#[N:13])=[CH:5][N:6]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:41])[CH3:40]
Reactant: CC1(C)OB(c2cccc3c2CCC3O[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: N#Cc1cc(-c2cnc(Br)s2)ccc1F
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: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(-c3ncc(-c4ccc(F)c(C#N)c4)s3)cccc21
Temperature: 85 °C
Yield: 32 %

Procedure:
Prepared using General Procedure 1. To 5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile THZ INT-4 (0.100 g, 0.35 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy) silane IND INT-8 (0.143 g, 0.38 mmol) and sodium carbonate (0.112 g, 1.1 mmol) in dioxane (1.8 mL) and H2O (0.2 mL) was added tetrakis(triphenylphosphine)palladium (0.041 g, 0.035 mmol). The solution was degassed with N2 and the reaction mixture heated at 85° C. for 6 h. Upon cooling, the reaction mixture was diluted with brine and washed with DCM (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (30% EA/Hexanes) to produce 0.05 g (32%) of 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-fluorobenzo-nitrile as a white solid. LCMS-ESI (m/z) calculated for C25H27FN2OSSi: 450.6; found 451.1 [M+H] +, tR=4.84 min (Method 3).
Reaction SMILES: Br[C:2]1[S:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9][CH2:8]2)=[CH:5][N:6]=1.Br[C:17]1[S:18][C:19]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[C:24]([C@H:33]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:34]([O:36][CH3:37])=[O:35])[C:23]([CH3:43])=[CH:22][C:20]=2[N:21]=1>C1(C)C=CC=CC=1.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.[Cu]I>[C:39]([O:38][C@@H:33]([C:24]1[C:23]([CH3:43])=[CH:22][C:20]2[N:21]=[C:17]([C:2]3[S:3][C:4]([N:7]4[CH2:12][CH2:11][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9][CH2:8]4)=[CH:5][N:6]=3)[S:18][C:19]=2[C:25]=1[C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)[C:34]([O:36][CH3:37])=[O:35])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)N1CCN(c2cnc(Br)s2)CC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ncc(N4CCN(C(C)C)CC4)s3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
A 5 mL microwave reaction tube was charged with 2-bromo-5-(4-isopropylpiperazin-1-yl)thiazole (12 mg, 0.041 mmol), Pd(PPh3)4 (7 mg, 15 mol %), CuI (4 mg, 30 mol %) and (SnBu3)2 (48 mg, 2 eq.) and toluene (0.5 mL). The reaction was heated to 110° C. in oil bath. (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (20 mg, 1.1 eq.) in toluene (4 mL) was added slowly (over 1.5 hours). The reaction was heated at 110° C. in oil bath for 2 hours. The reaction crude was partitioned between ethyl acetate and brine. The organic layer were concentrated and purified by reverse phase column chromatography (5-100% ACN/H2O+0.1% TFA) to give desired product. LCMS-ESI+: calc'd for C31H38ClN4O3S2: 613.2 (M+H+); Found: 613.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH2:15])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH:15][C:28]([C:25]3([C:23]4[CH:22]=[CH:21][C:20]5[O:16][CH2:17][O:18][C:19]=5[CH:24]=4)[CH2:27][CH2:26]3)=[O:29])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COc1ncccc1Cc1cnc(N)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ncccc1Cc1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1
Temperature: 78 °C
Reaction time: 12 h

Procedure:
5-(2-Methoxy-pyridin-3-ylmethyl)-thiazol-2-ylamine (221 mg, 1.00 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (206 g, 1.00 mmol) were dissolved in acetonitrile (5 mL) containing triethylamine (0.421 mL, 3.00 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 760 mg, 2.0 mmol) was added and the solution was allowed to stir at 78° C. for 12 hours. An aliquot of the crude product was purified by reverse-phase preparative liquid chromatography. ESI-MS m/z calc. 409.1. found; 410.3 (M+1)+ Retention time 3.23 minutes.
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1Cl>C(O)(C)C>[ClH:12].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Clc1ccncc1Cl
Reactant: Nn1ccc2ccccc21
Agent: Cl
Solvent: CC(C)O
Product: Clc1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 3,4-dichloropyridine hydrochloride in isopropanol at 100° C. for 4 hours in substantially the same manner as in Example 1, m.p. >230°.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([N:56]1[CH:60]=[C:59]([C:61]2[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=2)[CH:58]=[N:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[CH2:49]([N:56]1[CH:60]=[C:59]([C:61]2[CH:62]=[C:63]([NH:67][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:64]=[CH:65][CH:66]=2)[CH:58]=[N:57]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 52.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-benzyl-1H-pyrazol-4-yl)-phenylamine (0.016 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 55% yield: LCMS (ESI) m/z 438 (MH+).
Reaction SMILES: COC(C1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OCCCl)=O)=[C:8](C)[NH:9]C=1C)=O.[C:28]1([CH3:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:8][NH:9][CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccccc1
Product: CNCc1ccccc1

Procedure:
In 6 ml. of toluene were dissolved 2.0 g. of 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-β-chloroethyl ester 5-methyl ester and 1.3 g. of N-methylbenzylamine and the solution thus formed was refluxed for 5 hours under heating. After the reaction was over, the reaction mixture was mixed with 30 ml. of chloroform and 10 ml. of water and then the organic layer thus formed was separated and washed with 10 ml. of 10% hydrochloric acid and then with water. The organic solvent solution thus obtained was dried over anhydrous magnesium sulfate and then the solvent was distilled away under reduced pressure. The residue was added to 10 ml. of ethyl acetate and the mixture was stirred under cooling, whereby 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-β-(N-benzyl-N-methylamino)ethyl ester 5-methyl ester hydrochloride was crystallized. The amount of the product thus obtained was 1.6 g. The product recrystallized from a methanol-acetone mixture had a melting point of 180°-181° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](/[CH:15]=[CH:16]\[C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:14]=[C:13](/[CH:15]=[CH:16]\[C:17]([F:18])([F:19])[F:20])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C\C(F)(F)F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(/C=C\C(F)(F)F)cc1F

Procedure:
A solution of (Z)-tert-butyl 2-fluoro-4-(3,3,3-trifluoroprop-1-enyl)benzoate (35 mg, 0.12 mmol) in CH2Cl2 (5 mL) and TFA (0.5 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give a white solid. LC-MS: 2.86 min, 233.2 (M−1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@@H:3]([CH3:31])[CH2:2][NH:1][C:34](=[O:35])[C@@H:33]([OH:32])[CH2:38][CH2:37][OH:36])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@@H]1O
Product: C[C@@H](CNC(=O)[C@@H](O)CCO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 60 %

Procedure:
The procedure described in Example 63 was repeated using 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) and (S)-(−)-α-hydroxy-γ-butyrolactone to give the title compound in 60% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 1.43-1.57 (m, 3H), 1.71-1.86 (m, 1H), 3.33-3.53 (m, 3H), 3.65-3.79 (m, 1H), 3.88-4.00 (m, 1H), 4.36 (t, 1H), 4.85-4.96 (m, 1H), 5.29 (s, 2H), 5.45 (d, 1H), 7.24 (d, 2H), 7.28-7.41 (m, 2H), 7.59 (t, 2H), 7.71 (t, 1H), 7.87 (t, 1H), 8.10-8.21 (m, 2H), 8.48 (s, 1H), 8.59 (d, 1H), 9.99 (s, 1H); Mass spectrum MH+ 537.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][B:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[O:4][C:3]1([CH3:15])[CH3:14].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[F:17][C:18]1[CH:23]=[C:22]([CH:21]=[CH:20][CH:19]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([B:5]2[O:4][C:3]([CH3:15])([CH3:14])[C:2]([CH3:16])([CH3:1])[O:6]2)=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: OB(O)c1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(Oc3cccc(F)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
Into a 250 mL round-bottom flask, was placed a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g, 22.72 mmol, 1.00 equiv) in dichloromethane (100 mL), (3-fluorophenyl)boronic acid (3.5 g, 25.01 mmol, 1.10 equiv), Cu(AcO)2 (5 g), 4 A molecular sieves (15 g), and triethylamine (4.6 g). The resulting solution was stirred overnight at room temperature. The solids were filtered out and the filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:100-1:50) to give 1.8 g (25%) of 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:35]([CH2:36][O:37]CC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][CH2:26][CH2:25][CH2:24][C:21]1[N:20]2[C:15]3[CH:14]=[C:13]([C:6]4[C:5]5[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:8]([CH3:12])[CH:7]=4)[N:35]([CH2:36][OH:37])[C:16]=3[N:17]=[CH:18][C:19]2=[CH:23][N:22]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCNC(=O)OC(C)(C)C)n43)n1COCC[Si](C)(C)C)cn2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCN)n43)n1CO)cn2C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 3-(7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)propylcarbamate (0.347 g, 0.574 mmol, prepared using J.1 from Preparation #I.1 with 4-(tert-butoxycarbonylamino)butyric acid and L.1 with mercury(II) trifluoroacetate) in DCM (5 mL) at rt was added TFA (1.10 mL, 14.3 mmol). After about 16 h, the mixture was concentrated in vacuo to provide (1-(3-aminopropyl)-7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-6-yl)-methanol (0.232 g, 100%): LC/MS (Table 2, Method c) Rt=1.26 min; MS m/z 405 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:21][C:22](O)=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:25]([NH:27][CH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[CH3:26]>>[CH2:25]([N:27]([CH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[C:22](=[O:23])[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:12])=[O:11])[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:26]
Reactant: CCNCc1nccs1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cc1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH2:18]Cl)=O)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[S:30])[NH2:29])[CH2:24][CH2:23]1)=O.[OH-].[K+]>C(O)C.O>[C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[N:29]=[C:28]([N:25]4[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]4)[S:30][CH:18]=3)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCl)Cc1ccc(S(=O)c2ccccc2)cc1
Reactant: NC(=S)N1CCN(C=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(c1ccccc1)c1ccc(Cc2csc(N3CCNCC3)n2)cc1
Yield: 83.7 %

Procedure:
A solution of 14.6 g of 1-(4-phenylsulfinylphenyl)-3-chloroacetone and 8.7 g of 1-formyl-4-thiocarbamoyl piperazine, melting (Kofler) at 228° C., in 250 ml of ethanol at 90%, was boiled for one hour. There was added to the hot solution a solution of 9.3 g of KOH at 85% in 10 ml of water, and the mixture was refluxed for three hours, in order to hydrolyze the formyl protecting group. Then the solvent was evaporated off under reduced pressure, and the oily residue was taken up with 200 ml of a N hydrochloric acid solution. The insoluble matter was extracted with ether. The acid solution was alkalized with K2CO3, and the resulting base was extracted thrice with, each time, 50 ml of chloroform. The chloroform part was washed with water, then the solvent was evaporated off. There was obtained 16 g of 1-[4-(4-phenylsulfinylbenzyl)-2-thiazolyl]piperazine, as raw base, M.P. of its dihydrochloride: 158°-160° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]=[O:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[C:8]([CH:13]=[O:14])=[CH:9]1)(=[O:17])[CH3:16]
Reactant: O=Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1cc(C=O)c2ccc([N+](=O)[O-])cc21
Yield: 93.3 %

Procedure:
Substantially the same procedure as in Example 3 was repeated using 6-nitroindole-3-carboxaldehyde (2.3 g) and acetic anhydride (2.47 g) to give 1-acetyl-6-nitroindole-3-carboxaldehyde (2.62 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21]I>C1COCC1>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCCc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a mixture of [3-(4-fluoro-phenyl)-propyl]-carbamic acid tert-butyl ester (0.390 g, 1.540 mmol) and NaH (0.092 g, 2.310 mmol, 60% in mineral oil) in 10 mL of THF, was added via a syringe MeI (0.19 mL, 3.080 mmol). After stirring overnight at room temperature under N2, the reaction was quenched with NH4Cl solution (40 mL) and the resulting mixture extracted with dichloromethane (40 mL×3). The combined organic extracts were dried, filtered, and concentrated under reduced pressure. The product was isolated using Flash column chromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (0.417 g, >99% yield). GC-MS: tR=8.6 min; m/z 267 (M+).