Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1)=[O:4].[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1)[C:36](=[O:37])[CH2:35][C:30]1[NH:29][C:28]2[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=2[S:32](=[O:33])(=[O:34])[N:31]=1)=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)c(Cl)c1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1

Procedure:
(1R,2S)-2-(3-Chloro-4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (0.12 g, 0.42 mmol) was dissolved in anhydrous N,N-dimethylformamide (4.2 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.154 g, 0.46 mmol) was added followed by N-methylmorpholine (0.101 mL, 0.92 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.088 g, 0.46 mmol) was added portionwise and the mixture was stirred at 25° C. for 15 h. The reaction mixture was quenched by pouring into 1.0 M aqueous hydrochloric acid solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was concentrated in vacuo to afford the crude product, (1R,2S)-2-{(3-chloro-4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester, which was used directly in the next step without further purification. LC-MS (ESI) calcd for C24H26ClFN4O7S2 600.09, found 601.1 [M+H+].
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>O.O1CCCC1>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:14]=2[F:13])[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Fc1cccc(CBr)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(O)nc(SCc2cccc(F)c2F)n1
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 94.4 %

Procedure:
To a stirred suspension of 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (67.7 g) in a mixture of water (920 ml) and tetrahydrofuran (300 ml) was added aqueous sodium hydroxide solution (46-48% w/w; 24 ml) followed by water (40 ml). The resulting hazy, pale yellow solution was cooled to 20° C. before adding 2,3-difluorobenzyl bromide (83.0 g) uniformly over 25 minutes, to yield a white precipitate. The mixture was stirred at ambient temperature for 3.5 hours, the product collected and washed twice with a mixture of water (68 ml) and tetrahydrofuran (24 ml), to afford the title compound as a white solid (101.89 g).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CCN(C(C)C)C(C)C.[C:13]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33]([N:36]3[CH:40]=[C:39]([C:41](O)=[O:42])[CH:38]=[N:37]3)(=[O:35])=[O:34])=[CH:32][C:19]=2[N:18]=1)([CH3:16])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:13]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33]([N:36]3[CH:40]=[C:39]([C:41]([NH:3][CH2:1][CH3:2])=[O:42])[CH:38]=[N:37]3)(=[O:35])=[O:34])=[CH:32][C:19]=2[N:18]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1
Yield: 49.2 %

Procedure:
Following the same procedure in Example 24, Step A, using ethylamine (73 uL, 2.0 M in THF, 0.15 mmol), DIPEA (28 uL, 21 mg, 0.16 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.073 mmol) and HATU (44 mg, 0.12 mmol) in DMF (2.5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 17 mg (48%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.15 (t, J=7.23 Hz, 3 H), 1.40-1.57 (m, 4 H), 1.59 (s, 9H), 2.21-2.41 (m, 1 H), 2.79 (s, 1 H), 3.29-3.35 (m, 4 H), 3.84-3.95 (m, 2 H), 4.41 (d, J=7.42 Hz, 2 H), 7.91 (d, J=9.0 Hz, 1 H), 7.98 (dd, J=9.0, 1.7 Hz, 1 H), 8.03 (s, 1 H), 8.33 (d, J=1.56 Hz, 1 H), 8.74 (s, 1 H); MS (ESI) (M+H)+=474.0; Anal. Calcd for C23H31N5O4S+0.70 TFA+0.30 EtOAc+0.40H2O (590.66): C, 52.67; H, 5.96; N, 11.86. Found: C, 52.63; H, 5.99; N, 11.81.
Reaction SMILES: [CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:17][CH3:18])[C:9](=[O:19])[CH:8]([NH:20]C(OCC3C=CC=CC=3)=O)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)=O.CO.[Pd]>[NH2:20][CH:8]1[N:7]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH3:18])[C:9]1=[O:19]
Reactant: CCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCC2)c2ccccc21
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CCN1C(=O)C(N)N=C(C2CCCC2)c2ccccc21

Procedure:
5-Cyclopentyl-1,3-dihydro-1-ethyl-3(R,S)[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.5 g, 1.23 mmol) was dissolved in formic acid/methanol (50 ml of a 4.5% (v/v) solution), and added, over 5 min, to a stirred suspension of 10% palladium on carbon (200 mg, 40% (w/w)) in formic acid/methanol (10 ml). After 10 min the catalyst was removed by filtration, washed with methanol and acetone and the flitrate concentrated. The residue was partitioned between ethyl acetate (100 ml) and 10% sodium carbonate solution (100 ml). The organic phase was separated, dried (Na2SO4) and evaporated to give a clear oil which was used without further purification.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cc1ccccc1N
Product: Cc1ccccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 20.6 %

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 582 mg of 2-methylaniline in place of the 2-fluoroaniline. 76 mg of N-(2-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:12]1(/[C:18](=[CH:21]\[CH3:22])/[CH2:19]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:19]/[C:18](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:21]/[CH3:22])=[O:8])=[O:4]
Reactant: O=C(O)CNC(=O)C(F)(F)F
Reactant: C/C=C(/CO)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C(/COC(=O)CNC(=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
To a suspension of N-trifluoroacetylglycine (11, 3.68 g, 21.50 mmol) and (E)-2-phenyl-2-buten-1-ol (12, 2.68 g, 19.32 mmol) in DCM (60 mL) at −40° C. under N2 was added via cannula a solution of dicyclohexylcarbodiimide (4.43 g, 21.50 mmol) and 4-dimethylaminopyridine (0.269 g, 2.15 mmol) in DCM (60 mL). The solution was stirred at ambient temperature for 18 h and filtered, and the precipitate was washed with DCM (2×40 mL). The combined filtrate and washing was washed with 10% citric acid (2×25 mL), H2O (10 mL), 6% NaHCO3 (2×25 mL), and 5 M NaCl (20 mL), and dried, and the solvent was evaporated. The residue was chromatographed (silica gel, 150 g; 4:1 hexane-EtOAc) to afford 5.06 g (87%) of 13 as a pale yellow oil that solidified on standing: mp 49-50° C.; Rf0.66 (4:1 hexane-EtOAc); 1H NMR δ 7.37 (2H, t, J=7.5 Hz), 7.30 (1H, t, J=7.2 Hz), 7.18 (2H, d, J=7.6 Hz), 6.75 (1H, br s), 5.95 (1H, q, J=6.9 Hz), 4.91 (2H, s), 4.06 (2H, d, J=4.9 Hz), 1.66 (3H, d, J=6.9 Hz); 13C NMR δ 167.9, 156.7 (m), 137.3, 135.4, 135.4, 128.5, 128.4, 127.4, 116.9, 70.8, 41.4, 14.6; MS APCI+ m/z 302.1026 [M+H]+ (calcd for C14H15F3NO3, 302.1004); anal. C, 55.73, H, 4.93, N, 4.67%, calcd for C14H14F3NO3, C, 55.82, H, 4.68, N, 4.65%.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:8]=1[CH:9]=[CH2:1]
Reactant: CC(C)(C)c1ccc(C=O)c(Br)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (12.3 g, 33.7 mmol) in anhydrous THF (40 ml) was added n-butyl lithium (1.60 mol/l, hexane solution) (33.7 mmol, 21.1 ml) at 0° C. After 30 minutes at 0° C., to this was added 2-bromo-4-tert-butylbenzaldehyde (4.06 g, 16.8 mmol) (prepared according to J. Med. Chem. 2005, 48, 71-90) in anhydrous THF (10 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel, eluting with hexane, to afford the title compound (3.27 g, 81%) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](C(C)(C)C)[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:19]Br>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([Br:19])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
1,3,5-Tri-t-butylbenzene (150 g, 0.6 mol) was dissolved in 600 mL of carbon tetrachloride in a three-neck flask painted black to avoid light; The flask was equipped with an overhead stirrer, a thermometer, and an addition funnel under argon. Ferric chloride (3.0 g, 0.018 mol) was added and the solution was cooled to 0° C. A solution of bromine (120 g, 0.75 mol) dissolved in 200 mL of carbon tetrachloride was then added over a 2-hour period. The solution was stirred for an additional 1 hour at 0° C. and quenched with ice water. The layers were separated and the organics washed with 10% sodium hydroxide solution. The solution was then washed with salt brine and dried over magnesium sulfate. The solvent was removed under vacuum and the product was distilled through a 2-ft (60-cm) column under vacuum two times. The fractions boiling at 90°-110° C. at 0.4 mm Hg were combined and recrystallized from heptane to give 100 g of pure 3,5-di-t-butylbromobenzene (60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[C:42]([S:44](=[O:63])(=[O:62])[N:45](CC2C=CC(OC)=CC=2OC)[C:46]2[S:47][CH:48]=[N:49][N:50]=2)[C:41]([F:64])=[CH:40][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)[CH:22]=1.Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[CH:22]=2)=[CH:40][C:41]([F:64])=[C:42]([S:44]([NH:45][C:46]2[S:47][CH:48]=[N:49][N:50]=2)(=[O:63])=[O:62])[CH:43]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnc(N3CCNCC3)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
tert-Butyl 4-(4-(4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,3,4-thiadiazol-2-yl)sulfamoyl)-5-fluorophenoxy)-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 113, 340 mg, 0.361 mmol) was dissolved in methanol (1 mL) and a 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The resulting residue was purified by reverse phase chromatography using the ISCO™ system and acetonitrile/water 5/95-95/5 with 0.1% formic acid as eluent to afford the title compound (90 mg, 34%) as a white solid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:37][NH2:38])=[CH:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([N:37]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:38]3)=[CH:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccnc2cc(Cl)ccc12
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2cc(Cl)ccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=484.1 (M+H)+
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]2[C:8]3[CH:14]=[CH:13][N:12]([S:15]([C:18]4[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:9]=3[N:10]=[CH:11][C:6]2=[CH:5][N:4]=1.C1C(=O)N([Br:32])C(=O)C1.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:32][C:5]1[N:4]=[C:3]([CH3:2])[N:7]2[C:8]3[CH:14]=[CH:13][N:12]([S:15]([C:18]4[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=4)(=[O:16])=[O:17])[C:9]=3[N:10]=[CH:11][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C)n23)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C)n23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a mixture of 1-methyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (2.11 g, 5.81 mmol) in DMF (58 ml) was added NBS (1.03 g, 5.81 mmol). The mixture was stirred for about 2 h at rt. The mixture was poured into rapidly stirred water (˜300 mL). Saturated aqueous NaHCO3 (˜15 mL) was added and the mixture stirred for about 1 h. The solid was collected by filtration and washed with water (˜50 mL). The solid was dissolved in DCM (100 mL) and washed with saturated aqueous Na2CO3 (20 mL). The layers were separated and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (80 g Silicycle™ column) eluting with 10% EtOAc in DCM to give 3-bromo-1-methyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (1.62 g, 69%): LCMS (Table 2, Method b) Rt=2.52 min.; MS m/z: 404.96, 406 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH:28]([CH3:29])[CH3:30])([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of 4-fluoro-N2-pyridin-3-ylbenzene-1,2-diamine (685 mg, 3.0 mmol) in DCM (18 mL) at 0° C. were added (S)-2-tertbutoxycarbonylamino-3-methylbutyric acid (720 mg, 3.3 mmol), HOAt (0.450 g, 3.3 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.63 g, 3.3 mmol) and the resulting mixture stirred at 0° C. for 2 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-60% EtOAc in cyclohexane) to afford {(S)-1-[4-fluoro-2-(pyridin-3-ylamino)phenylcarbamoyl]-2-methylpropyl}carbamic acid tert-butyl ester (790 mg). LCMS (Method J): RT 2.10 min [M+H]+ 403.3
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:9]1([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Brc1ccnc(-c2ccccc2)c1
Yield: 43.3 %

Procedure:
A mixture was prepared of 2,4-dibromopyridine (10 g, 42.21 mmol), phenylboronic acid (5.1 g, 42.21 mmol), and potassium carbonate (11.7 g, 84.42 mmol) in 100 mL dimethoxyethane and 40 mL of water. Nitrogen was bubbled directly into the mixture for 30 minutes. Next, tetrakis(triphenylphosphine)palladium(0) was added (244 mg, 2.11 mmol) and the mixture was heated to reflux under nitrogen overnight. The mixture was cooled and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with 0, 2, and 5% ethyl acetate/hexanes. Obtained 4.28 g of a yellow liquid (43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27]C(N1C[C@@H](C)N2[C@H](CC3C2=NC(O)=CC=3)C1)=O)(C)(C)[CH3:24].[H-].[Na+].C(Br)C>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:27][CH2:23][CH3:24])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: [H-]
Agent: [Na+]
Solvent: CCBr
Product: CCOc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 22 intermediate b), from (4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and ethyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:15][OH:16])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCCC2=NO
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A solution of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (5 g, 28.4 mmol), hydroxylamine hydrochloride (2.366 g, 34.0 mmol) and sodium acetate (2.79 g, 34.0 mmol) in anhydrous methanol (20 mL) was heated at 80° C. (oil bath temp.) for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Next, 75 mL of water was added to the resulting solid and the contents were triturated and filtered. The solid was washed with addition water (2×50 mL), toluene (50 mL) and then dried for 80 h to yield 4.2 g of the oxime as a white solid. A second crop of additional product (1.1 g of pink solid) was obtained from the mother liquor. 1H NMR (400 MHz, CDCl3) δ ppm 1.83-1.91 (m, 2H) 2.70-2.83 (m, 4H) 3.81 (s, 3H) 6.66 (d, J=2.76 Hz, 1H) 6.77 (dd, J=8.78, 2.76 Hz, 1H) 7.83 (d, J=8.78 Hz, 1H) 8.32 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@H:4]([CH2:37][CH:38]([CH3:40])[CH3:39])[NH:5][C:6](=[O:36])[C@@H:7]([CH3:35])[NH:8][C:9](=[O:34])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)[NH:11]C(OC(C)(C)C)=O.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[CH3:1][O:2][C:3](=[O:41])[C@H:4]([CH2:37][CH:38]([CH3:40])[CH3:39])[NH:5][C:6](=[O:36])[C@@H:7]([CH3:35])[NH:8][C:9](=[O:34])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)[NH2:11]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1

Procedure:
Nα-t-butoxycarbonyl-O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester, 5.7 g., 10 mmol, in 20 ml. of dichloromethane and 50 ml. of trifluoroacetic acid are reacted together for 10 minutes at 25° C. The solution is evaporated and the residual oil used directly.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20]>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[CH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(Cl)c(Cl)c1
Yield: 71.2 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (3.0 g, 14.5 mmol) and 3,4-dichloroaniline (1.88 g, 11.6 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (2.90 g, 57%) was obtained.
Reaction SMILES: CS(O)(=O)=O.[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15][OH:16])=[CH:12][CH:11]=1)[CH3:8].[NH2:17][CH2:18][CH2:19][CH2:20]O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:17][CH2:18][CH2:19][CH2:20][O:16][CH2:15][C:13]1[O:14][C:10]([CH2:9][N:7]([CH3:6])[CH3:8])=[CH:11][CH:12]=1
Reactant: NCCCO
Reactant: CN(C)Cc1ccc(CO)o1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(COCCCN)o1
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
To a stirred solution of methanesulphonic acid (18 ml) in dry tetrahydrofuran (40 ml) kept at room temperature was added, with stirring, a mixture of 5-[(dimethylamino)methyl]-2-furanmethanol (4.65 g) and 3-amino-1-propanol (6.75 g). After 3 days the suspension was heated on a steam bath for 30 mins. Excess anhydrous sodium carbonate and ethyl acetate (100 ml) were added and the heating continued for 20 mins. The hot suspension was filtered and the residue washed with hot ethyl acetate (3×50 ml). The combined filtrates were evaporated to dryness, water (150 ml) added and the solution extracted with ethyl acetate (3×50 ml). The aqueous fraction was acidified with oxalic acid (5 g) and the solution evaporated to low bulk. Ethyl acetate (100 ml) and excess anhydrous sodium carbonate were added and the suspension heated to boiling point for 30 mins. The hot suspension was filtered and the combined filtrates and washings evaporated to dryness. The oily residue was distilled (100°-110°/0.2 mm) to give the title compound (2.76 g).