Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])[CH3:27]>>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1/[C:26](/[CH3:27])=[CH:25]/[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(2-Bromo-1-methyl-vinyl)-2,4-difluoro-benzene (279 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-2% MeOH-DCM. The product was further purified by HPLC. Yield: 14 mg. 1H NMR (CDCl3, freebase) δ (ppm): 7.40 (m, 1H), 7.22 (s, 1H), 7.10 (d, 1H), 7.0 (d, 1H), 6.90 (m, 2H), 6.70 (s, 1H), 3.70 (s, 2H), 2.85 (m, 4H), 2.60 (s, 3H), 2.45 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (example E.83) (3.6 g, 10.29 mmol) and commercially available 3-nitrophenylboronic acid (2.062 g, 12.35 mmol) according to the general procedure VI. Obtained as a light brown solid (2.1 g, 46%). MS (ISP) 437.2 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(=O)(OC(C)(C)C)[O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:15][C:12]([O:11][C:9]([N:1]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[C:9](=[O:8])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1nccs1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccs1
Yield: 79.9 %

Procedure:
A solution of 2-aminothiazole (5 g, 0.05 mol), (2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (27.8 g, 0.15 mol) and DMAP (100 mg) in THF (100 mL) was stirred at reflux overnight. The mixture was allowed to cool and concentrated in vacuo. The residue was chromatographed on silica, eluting with 8% ethyl acetate in hexane, to give the desired material as a white solid (12 g).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=2)=[N:11][NH:10]1.Cl.[CH:30]1([O:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH:30]1([O:35][CH:36]2[CH2:41][CH2:40][N:39]([C:26]([C:22]3[CH:21]=[C:20]([CH2:19][C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:9](=[O:8])[NH:10][N:11]=4)[CH:25]=[CH:24][N:23]=3)=[O:28])[CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCC(OC2CCNCC2)C1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccn1)N1CCC(OC2CCCC2)CC1
Temperature: 20 °C
Reaction time: 72 h
Yield: 8.3 %

Procedure:
Triethylamine (0.452 ml, 3.24 mmol) was added in one portion to 4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)picolinic acid (5) (304 mg, 1.08 mmol), 4-(cyclopentyloxy)piperidine hydrochloride (183 mg, 1.08 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (533 mg, 1.41 mmol) in DMA (3 ml) at 20° C. under air. The resulting mixture was stirred at 20° C. for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (39 mg, 8.3% yield); 1H NMR (400.132 MHz, DMSO) δ 1.28-1.74 (11H, m), 1.82-1.88 (1H, m), 3.08-3.14 (1H, m), 3.20-3.27 (1H, m), 3.44-3.49 (1H, m), 3.53-3.59 (1H, m), 3.96-4.05 (2H, m), 4.40 (2H, s), 7.39 (1H, d), 7.49 (1H, s), 7.83-7.96 (3H, m), 8.28 (1H, d), 8.47 (1H, d), 12.60 (1H, s); m/z (LC-MS, ESI+), RT=1.88 (M+H 433.1).
Reaction SMILES: [C:1]([O:4][CH:5]([C:23](=[O:32])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH2:31])[CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])(=[O:3])[CH3:2].[C:33]([CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][C:45](O)=[O:46])([OH:35])=[O:34].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[C:1]([O:4][CH:5]([CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])[C:23](=[O:32])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:45]([CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][C:33]([OH:35])=[O:34])=[O:46])(=[O:3])[CH3:2]
Reactant: O=C(O)COCCOCCOCC(=O)O
Reactant: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCN
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCNC(=O)COCCOCCOCC(=O)O

Procedure:
A solution of 500 mg of 2,3,4-triacetoxy-1-{2-[2-(2-aminoethoxy)ethoxy]acetyl}-5-hydroxypentyl acetate 23, 1.15 g of [2-(2-carboxymethoxyethoxy)ethoxy]acetic acid, 400 μl of diisopropylcarbodiimide and 288 mg of hydroxybenzotriazole in 20 ml of methylene chloride is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) 80/20>10/90). This gives 24: C28H45NO18 (683.67) MS (ESI) 684 (M+H)
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([CH3:38])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH3:20])=[C:15]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:14]=1)=[O:11])C)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:24]1([S:21]([N:19]([CH3:20])[C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[CH:9]([NH:7][CH3:6])[CH3:38])=[N:14][C:15]=2[C:30]#[C:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:22])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C(=O)Nc1ccc(N(C)S(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C(=O)Nc1ccc(N(C)S(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-[benzenesulfonyl(methyl)amino]-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate F5a (25 mg) and DCM:TFA (9:1, 3 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 7 mg. HPLC-MS: M+H=449; tR=1.49 min (*Method—1).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@H]2O[C@@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)([O-])=O)[C@H](O)[C@@H]2O)C=C(C(N)=O)C=1.[OH-].[Na+]>P([O-])([O-])([O-])=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: NC(=O)c1ccc[n+]([C@H]2O[C@@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@H](O)[C@@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: O[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A liquid medium having the composition given in Example 1 was prepared and distributed in 50-ml portions into fifty 500-ml Sakaguchi flasks and steam-sterilized at 120° C. for 20 minutes. The contents of each flask was aseptically inoculated with 1 ml of a fluid culture obtained by cultivating Trichosporon fermentans ATCC 10675 in the same manner as in Example 1, and shake-culture was carried out at 30° C. for 24 hours. Cells were harvested from the resultant culture fluids by centrifugation and suspended in 500 ml of 100 mM phosphate buffer (pH 6.5). To this suspension, there were added 5 g of N-benzyl-3-pyrrolidinone, 10 g of glucose, 275 mg of oxidized form nicotinamide adenine dinucleotide phosphate (product of Kohjin Co.) and 1,420 units of glucose dehydrogenase (product of Amano Pharmaceutical Co.), and the reaction was allowed to proceed at 30° C. with stirring for 48 hours, while the reaction mixture was maintained at pH 6.5 with 6N aqueous sodium hydroxide solution. Thereafter, the reaction mixture was extracted with 2.5 L of ethyl acetate, and the aqueous layer was further extracted with 1 L of ethyl acetate. The organic layers were combined and dehydrated over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by subjecting the same to silica gel column chromatography (eluent: ethyl acetate/methanol=2/1) to give 2.5 g of (S)-N-benzyl-3-pyrrolidinol. The yield was 49%, the optical purity was 96% ee, the boiling point was 132 to 137° C./3 mm Hg, and the optical rotation [α]D20 was −3.73° (CH3OH, c=5). 1H-NMR δ CDCl3): 1.63-1.76 (1H, m), 2.09-2.21 (1H, m), 2.26-2.37 (1H, m), 2.51-2.64 (2H, m), 2.75-2.85 (1H, m), 3.38 (1H, brs), 3.61 (2H, s), 4.24-4.33 (1H, m), 7.19-7.37 (5H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=O)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([Cl:21])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2c1CN(Cc1ccccc1)CC2

Procedure:
Various 4-alkylamino-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines are prepared using a general procedure shown in Scheme 3. 6-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one is treated with POCl3 to give 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine which is treated with sodium methoxide to give 6-benzyl-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. Debenzylation and reacting the product with an appropriate 2-halo-pyridine under SNAr or Buchwald coupling reaction conditions gives the 4-methoxy-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine which is reacted with POCl3/POBr3. Displacement of the resultant 4-halo group using various alkylamines via SNAr displacement can afford various 4-alkylamino-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32](=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1)[CH3:30]>>[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32]([N:23]1[CH2:24][CH2:25][CH:20]([C@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:33])[CH3:30]
Reactant: C[C@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: C[C@H](OC(=O)N1CCC([C@@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described in Example 1. LC (method 2): tR=0.92 min; Mass spectrum (ESI+): m/z=518 [M+H]+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]([C:9]1[CH:10]=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2[O:16][C:15](=[O:17])[CH:14](O)[C:13]=2[CH:19]=1)([CH3:8])([CH3:7])[CH3:6].[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>O>[C:5]([C:9]1[CH:10]=[C:11]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]2[O:16][C:15](=[O:17])[CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:13]=2[CH:19]=1)([CH3:6])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccccc1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
73.3 g (0.55 mol) of ground aluminium trichloride are added over 25 minutes to a solution of 131.2 g (0.50 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 250 ml (2.82 mol) of benzene and the reaction mixture is heated for 1.5 hours to reflux temperature and then refluxed for 1.5 hours. The reaction mixture is cooled to room temperature and then, cautiously with cooling, 200 ml of water are added, followed by the addition of concentrated hydrochloric acid until a homogeneous two-phase mixture forms. The organic phase is separated, washed with water, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 97.8 g (64%) of 5,7-di-tert-butyl-3-phenyl-3H-benzofuran-2-one, m.p. 116°-119° C. (compound (108), Table 1).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12](SC)=[C:13]([C:16]#[N:17])[C:14]#[N:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[NH2:21][NH2:22]>CO>[NH2:15][C:14]1[NH:22][N:21]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:13]=1[C:16]#[N:17]
Reactant: NN
Reactant: CSC(NCCNC(=O)OC(C)(C)C)=C(C#N)C#N
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1n[nH]c(N)c1C#N

Procedure:
A mixture of 80.81 g (286.4 mol) of 3-[2-(Boc-amino)-ethylamino]-2-cyano-3-methylmercapto-acrylonitrile, 14.9 ml (300.7 mmol) of hydrazine hydrate and 500 ml of methanol is heated under reflux for 4 hours and then concentrated by evaporation in vacuo at about 50° C., yielding 5-amino-3-[2-(Boc-amino)-ethylamino]-4-cyano-pyrazole; TLC-Rf=0.27 (methylene chloride/methanol [9:1]).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][C:22]([C:23]([OH:25])=O)=[C:11]2[CH2:10][N:9]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:32]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][C:22]([C:23]([NH2:32])=[O:25])=[C:11]2[CH2:10][N:9]=1
Reactant: N
Reactant: O=C(O)c1ncn2c1CN=C(c1ccccc1Br)c1cc(F)ccc1-2
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: NC(=O)c1ncn2c1CN=C(c1ccccc1Br)c1cc(F)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3 g (7.5 mmol) of 6-(2-bromophenyl)-8-fluoro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 300 mL of methylene chloride and 2.25 g (10.8 mmol) of phosphorus pentachloride was stirred at room temperature for 2 hours. Ammonia gas was then introduced until the mixture was basic. After layering with 20 mL of concentrated aqueous ammonia, the mixture was stirred for 15 minutes. The methylene chloride was washed with water, dried and evaporated. The residue was crystallized from ethanol/water to yield 2.4 g of product having the above formula. A second crop of 0.4 g was obtained from the mother liquor for a total yield of 2.8 g. For analysis, a sample of the product was recrystallized from methylene chloride/ethanol and had m.p. 298°-299° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[C:34](F)=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:32])=[CH:26][CH:25]=1)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=O)(C)(C)C.Cl.Cl.[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([CH2:51][NH2:52])=[C:45]2[CH:44]=[CH:43]1>>[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([CH2:51][NH:52][C:34]3[N:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:31]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:15]([O:14][CH2:13][C@@H:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)([C:16]([F:19])([F:17])[F:18])[C:20]([F:21])([F:22])[F:23])=[CH:29][CH:28]=3)=[O:32])=[C:45]2[CH:44]=[CH:43]1
Reactant: NCc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COC(c1ccc(NC(=O)c2cccnc2F)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Product: O=C(Nc1ccc(C(OC[C@@H]2CCCN2)(C(F)(F)F)C(F)(F)F)cc1)c1cccnc1NCc1ccnc2[nH]ccc12

Procedure:
The titled compound was prepared from (S)-2-(2,2,2-trifluoro-1-{4-[(2-fluoro-pyridine-3-carbonyl)-amino]-phenyl}-1-trifluoromethyl-ethoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Example 1. MS (ES+): 593 (M+H). Calc'd. for C28H26F6N6O2—592.54.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([F:16])[CH:10]=2)[CH3:6]>C(O)(=O)C>[CH2:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([F:16])=[CH:12][CH:13]=2)[NH:8]1)[CH3:6]
Reactant: CCc1cc2ccc(F)cc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1Cc2ccc(F)cc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.7 g (40 mmol) sodium cyanoborohydride were added to 1.6 g (10 mmol) 2-ethyl-6-fluoro-1H-indole in 20 mL conc. acetic acid and the mixture was stirred for 1 h at RT. The reaction mixture was evaporated down. The residue was mixed with 20 mL of a 4N HCl solution and stirred for 1 h at RT. Then 45 mL of a 4N sodium hydroxide solution was slowly added while cooling with ice and the mixture was extracted with ethyl acetate. The organic phase was dried on sodium sulphate and evaporated down.
Reaction SMILES: BrC1C=CC(NC2C(C(O)=O)=CN=C(Cl)C=2Cl)=C(Cl)C=1.O.[NH2:22][NH2:23].[CH2:24]([O:26][C:27](=[O:45])[C:28]1[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=2[Cl:42])=[C:32]([Cl:43])[C:31]([Cl:44])=[N:30][CH:29]=1)[CH3:25]>CN(C)C(=O)C.CCOC(C)=O>[CH2:24]([O:26][C:27](=[O:45])[C:28]1[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=2[Cl:42])=[C:32]([Cl:43])[C:31]([Cl:44])=[N:30][CH:29]=1)[CH3:25].[CH2:24]([O:26][C:27](=[O:45])[C:28]1[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=2[Cl:42])=[C:32]([Cl:43])[C:31]([NH:22][NH2:23])=[N:30][CH:29]=1)[CH3:25]
Reactant: NN
Agent: CCOC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(NN)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
4-(4-Bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid ethyl ester (48) was prepared by standard methods from 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid. Hydrazine monohydrate (0.59 mL, 12.16 mmol) was added to a solution of 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid ethyl ester (48) (1.72 g, 4.05 mmol) in N,N-dimethylacetamide (20 mL). After stirring at 90° C. for 1 hour, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated. Purification by flash column chromatography using the Biotage system (20:1 CH2Cl2:EtOAc) provided the desired product (49) (307 mg, 18%).
Reaction SMILES: [CH:1]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:17]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:14]([CH3:16])[CH3:15])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1)([CH3:18])[CH3:19]
Reactant: CC(C)[Si](OCC1CCC(O)CC1)(C(C)C)C(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)[Si](OCC1CCC(=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
To a solution of 15.5 g (54 mmol) of the alcohol from Step B in dichloromethane was added 20 g of Celite and 17.5 g (81 mmol) of pyridinium chlorochromate. The reaction mixture was stirred at room temperature for a 4 h period, and then filtered. The solids were washed with dichloromethane and the combined organic phases were concentrated. The residue was purified by flash chromatography on silica gel (15% ethyl acetate/hexane) to give 13 g (85%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 3.63 (d, 2H, J=4.9 Hz), 2.49–2.32 (m, 4H), 2.12 (m, 2H), 1.96 (m, 1H), 1.49 (m, 2H) 1.07 (d, 18H, J=5.5 hz), 1.06 (m, 3H).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[K].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([N+]([O-])=O)[CH:9]=1.O>CN(C)C=O>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:9]=1
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)=NO
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=NOc1cc(Cl)ccc1C#N
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
In 75 ml of dry N,N-dimethylformamide was dissolved acetone oxime (1.21 g), followed by potassium tertiaryl butoxide (1.85 g) and stirred under nitrogen. After 30 minutes, 4-chloro-2-nitro-benzonitrile (2.00 g) was added. After an additional 30 minutes the reaction was poured into water (500 ml) and filtered. The solid was collected and dissolved in DCM (250 ml), dried (MgSO4), and concentrated in vacuo. The resulting solid was recrystallized from ethanol to yield 1.5 g of the product, m.p. 83°-84° C.