Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[Cl:21][C:22]1[CH:44]=[C:43]([F:45])[C:42]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[CH:41][C:23]=1[C:24]([NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([C:38]([OH:40])=O)[CH:28]=1)=[O:25].C(N(CC)C(C)C)(C)C.[CH2:61]([CH2:63][NH2:64])[OH:62]>CN(C=O)C>[Cl:21][C:22]1[CH:44]=[C:43]([F:45])[C:42]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[CH:41][C:23]=1[C:24]([NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([C:38]([NH:64][CH2:63][CH2:61][OH:62])=[O:40])[CH:28]=1)=[O:25]
Reactant: NCCO
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
TPTU (510 mg, 1.72 mmol) and 5-(2-chloro-4-fluoro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 108, 500 mg, 1.14 mmol) were dissolved in DMF (2.5 mL) at 0° C. N,N-diisopropylethylamine (0.6 mL, 3.43 mmol) was then added and the mixture stirred at 0° C. for 15 minutes. Ethanolamine (99.5 mL, 1.65 mmol) was then added and the mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and the resulting brown solid triturated with dichloromethane/TBME/heptane (4:2:0.5, 5 mL) to give a white solid, which was further triturated with MeOH (5 mL) to afford the title compound as a white solid (262 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N+:6]=1[O-])=[O:4].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c2ccccc2cc[n+]1[O-]
Product: COC(=O)c1nc(Cl)cc2ccccc12
Temperature: 100 °C
Yield: 49 %

Procedure:
A mixture of 1-(methoxycarbonyl)isoquinoline 2-oxide (9.5 g, 46.75 mmol) and POCl3 (50 mL) was heated at 100° C. for 4 hours. The reaction mixture was subsequently cooled and concentrated, and the crude product was purified by silica gel chromatography eluting with petroleum ether and EtOAc (15:1) to give the title compound as a white solid (5.1 g, 49%). ESI-MS m/z [M+H]+ 222.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]1([N:20]2[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]2)[C:12]2[N:13]([CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:15][N:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([NH:25][C@H:22]2[CH2:23][CH2:24][N:20]([C:11]3[C:12]4[N:13]([CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:15][N:16]=3)[CH2:21]2)=[O:10])=[N:4][CH:3]=1
Reactant: N[C@H]1CCN(c2nccn3cccc23)C1
Reactant: O=C(O)c1ncc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
To a solution of 5-bromopyrimidine-2-carboxylic acid (2.0 g, 9.9 mmol, 1 eq) and (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (2.7 g, 9.9 mmol, 1 eq) in 20 mL of DMSO was added triethylamine (5.4 mL, 39 mmol, 3.9 eq) and HATU (4.1 g, 11 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by silica gel flash chromatography (EtoAc:MeOH 2:3) to produce (S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (5.0 g, 1.3 mmol, 13%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl>[C:5]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][CH2:10][CH2:9][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCCC(CCCc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 500-ml-three-necked round-bottomed flask, with an efficient cooling was charged with aluminium chloride (5.82 g, 43.67 mmol) and dichloromethane (100 ml). Acetyl chloride (3.42 g, 43.67 mmol) was added to the vigorously stirred reaction mixture over a period of 15 minutes. Pentadecyl benzene (10 g, 34.66 mmol) was added over a period of 30 minutes; the clear solution was stirred at 0° C. for 2 hours and allowed to warm to room temperature. The reaction mixture was poured in ice and extracted with dichloromethane (3×100 ml), the combined organic layers was washed with 1 N hydrochloric acid (2×30 ml) and water (3×50 ml), dried over sodium sulfate and the solvent was evaporated to obtain 4-acetyl pentadecyl benzene as a low melting faint yellow solid. The yield was 10 g (87% of theoretical).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:24]=[CH:23][C:12]2[C@:13]3([CH3:22])[C@@H:18]([CH2:19][CH2:20][C:11]=2[CH:10]=1)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)#[N:2].[C:25](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:25][N:17]1[C@H:18]2[C@@:13]([CH3:22])([C:12]3[CH:23]=[CH:24][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][C:11]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:21]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccccc3C#N)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccccc4C#N)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-cyanophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (55 mg, 0.17 mmol), 0.4 mL of t-butanol, and potassium t-butoxide (58 mg, 0.51 mmol). Methyl iodide (0.034 mL, 0.54 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 50 mg (87%) of the title compound as a white solid. mp 54°-55°. FDMS: m/e=330. α[D]589 =+74.33 (c=0.36, chloroform).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:36]([CH3:37])=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][C:5]=1[CH3:38].[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[S:48])=[CH:42][CH:41]=1.C(N(CC)CC)C>O1CCCC1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([NH:3][C:4]2[C:5]([CH3:38])=[CH:6][C:7]([O:8][C:9]3[CH:10]=[CH:11][C:12]4[N:16]=[C:15]([CH2:17][O:18][C:19]5[CH:20]=[CH:21][C:22]([CH2:23][CH:24]6[S:28][C:27](=[O:29])[NH:26][C:25]6=[O:30])=[CH:31][CH:32]=5)[N:14]([CH3:33])[C:13]=4[CH:34]=3)=[CH:35][C:36]=2[CH3:37])=[S:48])=[CH:42][CH:41]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1NC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.9 %

Procedure:
A mixture of 5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (288 mg), 4-chlorophenyl isothiocyanate (102 mg), triethylamine (121 mg) and anhydrous tetrahydrofuran (10 ml) was stirred at room temperature for 23 hours. The reaction mixture was concentrated and diluted with water. The precipitate was isolated by filtration and then chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1 as the eluant to afford the title compound (215 mg, mp 160-162° C.).
Reaction SMILES: [CH:1]([C@@H:4]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:12]=2[N+:25]([O-])=O)[CH2:7][CH2:6][N:5]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:3])[CH3:2]>C1COCC1.CO.[Ni]>[NH2:25][C:12]1[CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:4]([CH:1]([CH3:2])[CH3:3])[C:9]1=[O:10]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a 1 L round-bottom flask containing (R)-tert-butyl 2-isopropyl-4-(4-(methoxycarbonyl)-5-(methylsulfonyl)-2-nitrophenyl)-3-oxopiperazine-1-carboxylate (26.3 g, 0.0526 mol) in THF (200 mL) and methanol (200 mL) was added Raney Nickel (in H2O, 4 g). The mixture was stirred under H2 (30 psi) at rt overnight. The mixture was filtered and concentrated under vacuum to give (R)-tert-butyl 4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (24.7 g, 100% yield) as a yellow solid. The residue was used directly for the next step without further purification. LC-MS MS (ESI) m/z 414.0 [M−56+H]+, 492.0 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 7.77 (brs, 1H), 7.04 (s, 1H), 4.68-4.45 (m, 1H), 4.45-4.38 (m, 2H), 3.92 (s, 3H), 3.70-3.58 (m, 1H), 3.58-3.41 (m, 1H), 3.30 (s, 3H), 2.49-2.25 (m, 1H), 1.50 (s, 9H), 1.12 (d, J=6.9 Hz, 3H), 1.05 (d, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16](O)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)=[CH:8]2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[CH3:37][NH:38][OH:39].C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:38]([OH:39])[CH3:37])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CNO
Reactant: O=C1CN(Cc2cn(Cc3ccc(F)cc3)c3cnc(C(=O)O)cc23)CCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(O)C(=O)c1cc2c(CN3CCNC(=O)C3)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 5 °C
Reaction time: 1.17 h
Yield: 79.6 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (9.0 g 23.50 mmol) in anhydrous DMF (285 mL) was added CDMT (4.95 g 28.20 mmol 1.2 eq.) and NMM (N-methyl morpholine) (2.85 g 28.2 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 70 min. N-Methylhydroxylamine hydrochloride (23.6 g 282.0 mmol 12.0 eq) was added and stirring continued for 3 hours. The reaction was judged to be complete by HPLC-MS analysis, and was quenched by adding water (100 mL) to the reaction mixture. The volatiles were removed in vacuo (ca. 2 torr, at 60° C.) to give a residue. Saturated aqueous sodium bicarbonate (120 mL) was added to neutralize to pH 7. White solid precipitated out, and the mixture was cooled to 5° C. The solid was filtered, washed with cold water (100 mL), and dried in vacuo to afford 7.7 g (85%) of 1-(4-fluorobenzyl)-N-hydroxy-N-methyl-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide at >95% purity by 1HNMR analysis. To obtain 99% purity, 7.7 g of the product was dissolved in a boiling mixture (700 mL) of methanol and isopropanol (1:9). The hot solution was filtered to remove trace impurities, and the filtrate was allowed to cool to room temperature. The product crystallized out as needle-like crystals, which was filtered, washed with isopropanol, and dried in vacuo to afford (3.0 g) 99% purity. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—2.27 min, m/e=412.30 (M+H+, base). 1H NMR (400 MHz, DMSO-D6) d ppm 2.55 (t, J=5.29 Hz, 2H) 2.92 (s, 2H) 3.11 (s, 2H) 3.32 (s, 3H) 3.73 (s, 2H) 5.54 (s, 2H) 7.16 (t, J=8.81 Hz, 2H) 7.35 (dd, J=8.56, 5.54 Hz, 2H) 7.71 (s, 1H) 7.83 (s, 1H) 8.09 (s, 1H) 8.86 (s, 1H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[N:7][CH:8]=1.P(Br)(Br)([Br:22])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:22][C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[N:7][CH:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(Br)cnn1
Yield: 46.8 %

Procedure:
5-Methoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine(Compound No. 5, 5.0 g, 0.0182 mole) and phosphorus oxybromide (5.7 g, 0.02 mole) were refluxed under N2 in toluene (100 mL) for 3.5 hours. The mixture was poured into ethyl acetate and extracted 2×200 mL with water. The organic layer was then extracted with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated in vacuo to give a crude oil. The oil was purified by chromatography on silica gel to give 5-bromo-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5yl]oxy]pyridazine (2.75 g, 47% yield) as a brown solid which was used directly in the following step.
Reaction SMILES: [Br:1][C:2]1[C:3](Br)=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].Cl>CCOCC>[Br:1][C:2]1[CH:7]=[C:6]([Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:5]=[C:4]([Br:8])[CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cccc(Br)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(Br)cc(Br)c1
Temperature: -55 °C
Reaction time: 0.58 h

Procedure:
42.4 g of Tribromobenzene (134.6 mmol) was dissolved in 600 mL Et2O. The solution was chilled to −55° C., at which temperature starting material precipitated. 54 mL of n-BuLi (2.5 M in hexanes, 135 mmol) were added within 20 minutes. After stirring for 35 minutes at −52° C., 20 ml TMSCl (158 mmol) and 20 mL Et2O were added within 7 minutes. The suspension turned into a solution at −42° C., and a fine precipitate appeared at −30° C. The suspension was stirred overnight at room temperature. 100 mL 2M HCl were used to hydrolyze the mixture. After stirring for 30 minutes, the Et2O-phase was dried with MgSO4, filtered, and solvent evaporated until compound crystallized out of solution. The flask was stored overnight at +4° C. The crystalline compound was filtered, washed with a small amount cold pentane, and dried under vacuo. A second fraction of crystalline compound was obtained from the filtrate. Yield: 31.9 g (103.5 mmol, 77%). 1H-NMR (CHCl3=7.24 ppm): δ7.62 (t, 1H), 7.49 (d, 2H), 0.25 (s, 3×3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[S:30][C:29]([C:31]([OH:33])=O)=[CH:28][CH:27]=1.[CH:34]([N:47]1[CH2:50][C:49]2([CH2:55][NH:54][CH2:53][CH2:52][O:51]2)[CH2:48]1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C=O)C>[CH:34]([N:47]1[CH2:50][C:49]2([CH2:55][N:54]([C:31]([C:29]3[S:30][C:26]([CH3:25])=[CH:27][CH:28]=3)=[O:33])[CH2:53][CH2:52][O:51]2)[CH2:48]1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: c1ccc(C(c2ccccc2)N2CC3(CNCCO3)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCOC3(C2)CN(C(c2ccccc2)c2ccccc2)C3)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (2.267 g) was added in one portion to a solution of 5-methylthiophene-2-carboxylic acid (0.652 g) and 2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonane (example 33, step f) (1.35 g) and triethylamine (1.917 mL) in DMF (20 mL) at 0° C. The cooling bath was removed and the mixture stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine before being dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0.4 to 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.5 g.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][NH2:39]>CS(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([NH:39][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: NCc1ccccn1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NCc3ccccn3)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.95 mmol) in DMSO (5 mL) was added DIEA (245 mg, 1.90 mmol) and pyridin-2-ylmethanamine (124 mg, 1.15 mmol), and the reaction was stirred overnight at 90° C. in an oil bath. The solids were precipitated from water (50 mL), collected by filtration, washed with AcOEt (10 mL), and dried to afford methyl 2-(4-fluorophenyl)-3-[(pyridin-2-ylmethyl)amino]quinoxaline-6-carboxylate as a yellow solid (200 mg, 81%).
Reaction SMILES: C([O:4][C:5]1[CH:38]=[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([S:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)[N:7]2[N:6]=1)C=C.C([O-])=O.[NH4+]>CO.[Pd].CCOC(C)=O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([S:13][C:12]4[N:7]5[N:6]=[C:5]([OH:4])[CH:38]=[C:8]5[N:9]=[CH:10][CH:11]=4)=[CH:19][CH:18]=3)=[N:22][N:23]=2)=[CH:32][CH:33]=1
Reactant: C=CCOc1cc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)n2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1cc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)n2n1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(4-(2-(allyloxy)pyrazolo[1,5-a]pyrimidin-7-ylthio)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine (0.110 g, 0.20 mmol, Example 4) and ammonium formate (130 mg, 2.0 mmol) in MeOH (7 mL) was added a slurry of 10% palladium on carbon, (44 mg) in EtOAc (1 mL). The mixture was heated to 65° C. After 8 hrs, the mixture was cooled to RT, filtered over celite, concentrated in vacuo, and purified by silica gel chromatography using 5-15% MeOH in CH2Cl2 with 1% NH4OH to afford 7-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)pyrazolo[1,5-a]pyrimidin-2-ol as a light yellow solid. MS: Found M+H+=497.0.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[F:7][C:8]1[C:21]([NH:22][C:23](=O)[CH3:24])=[CH:20][C:11]2[N:12]([CH2:17][C:18]#[CH:19])[C:13](=[O:16])[CH2:14][O:15][C:10]=2[CH:9]=1.P(Cl)(Cl)([Cl:28])=O>C1C=CC=CC=1>[F:7][C:8]1[C:21]([N:22]=[C:23]([Cl:28])[CH3:24])=[CH:20][C:11]2[N:12]([CH2:17][C:18]#[CH:19])[C:13](=[O:16])[CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(C)=O)cc21
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: C#CCN1C(=O)COc2cc(F)c(N=C(C)Cl)cc21
Reaction time: 1 h

Procedure:
First, 10 ml of benzene and 0.4 g of phosphorus pentachloride were added to 0.5 g of N-(7-fluoro-4-propargyl-2H-1,4-benzoxazine-3(4H)-one-6-yl)-acetamide, and the stirring was continued for 1.0 hr at 60° C. After letting the mixture stand to cool the same, the produced phosphorus oxychloride and benzene were distilled out under reduced pressure to quantitatively obtain N-(7-fluoro-4-propargyl-2H-1,4-benzoxazine-3(4H)-one-6-yl)-acetimidoylchloride.
Reaction SMILES: [Br-].C[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.C([Li])CCC.C[O:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:45]C)[CH:44]=1)[CH:40]=O.O>O1CCCC1>[OH:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[CH:40]/[C:39]2[CH:42]=[C:43]([OH:45])[CH:44]=[C:37]([OH:36])[CH:38]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 4-methoxy-benzyltriphenylphosphonium bromide (12.5 g) in anhydrous tetrahydrofuran (200 mL) at −78° C. was added n-butyllithium (2.44 M, 1.0 equiv), and the resulting red solution was stirred under argon for 2-4 h. A solution of 3,5-dimethoxybenzaldehyde (4.5 g) in tetrahydrofuran was added dropwise over 30 min and the mixture stirred for 6-15 h. The resulting cream suspension was poured into water and extracted with dichloromethane. The organic phase was washed with water, and removal of the solvent in vacuo afforded an oil. The oil was separated by flash column chromatography (49:1 hexane/ethyl acetate). The cis-stilbene eluted first as a clear oil followed by the trans isomer as a colorless solid or oil. Overall yield: 91%. To a solution of the trans isomer (3.1. g) in anhydrous dichloromethane (150 mL) at −78° C. was added (dropwise) boron tribromide (1.0 M, 34.5 mL), and the resulting red solution was stirred under argon for 30 min. The solution was poured into water and extracted with dichloromethane. The organic phase was washed with water, and removal of the solvent in vacuo afforded an oil, which was separated by flash column chromatography (1:1 hexane/ethyl acetate) to afford a colorless solid (2.26 g, 86%): mp 260° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1.C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1cc(Cl)nc(C)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CCN(c2cc(C)nc(C)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
2,6-Dimethyl-4-chloro-pyrimidine (1.0 g) in ethanol (10 ml) was added slowly to a solution of ethyl isonipecotate (1.1 g) and triethylamine (2.0 ml) in ethanol (20 ml). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water, washed with water (2×50 ml), dried and evaporated to give 1-(2,6-dimethylpyrimidin-4-yl)-4-(ethoxycarbonyl)piperidine as an oil (1.71 g); NMR (CDCl3): 1.25 (t, 3H), 1.65-1.80 (m, 4H), 1.95-2.00 (m, 2H), 2.55 (s, 3H), 2.45 (s, 3H), 2.50-2.60 (m, 1H), 3.00 (dt, 2H), 4.15 (q, 2H), 4.35 (d, 2H), 6.2 (s, 1H).