Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:30])[CH:14]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:15](=O)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:30])[CH:14]([C:15]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:17]2[C:16]=1[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:11]
Reactant: CCOC(=O)C(C(=O)C1CCCCC1=O)C1CCCCC1
Reactant: NNc1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Yield: 46 %

Procedure:
(4-Chloro-phenyl)-hydrazine (100 mg, 700 μmol; CAS Reg. No. 1073-69-4) was added to a solution of 2-cyclohexyl-3-oxo-3-(2-oxo-cyclohexyl)-propionic acid ethyl ester (206 mg, 700 μmol) in ethanol (4.7 ml). The reaction mixture was heated under reflux conditions for 6 h. The solvent was removed under reduced pressure. The residue was taken up in ice water/brine 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a brown oil which was purified by preparative thick layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (130 mg, 324 μmol; 46%) as orange solid. MS: m/e=401.2 [M+H+].
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.ClCCl.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C.CO>[Br:22][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
1-(tert-Butyl) 2-methyl (2S,4R)-4-hydroxytetrahydro-1H-1,2-pyrroledicarboxylate (3) (2.0 g, 8.15 mmol) was weighed into an oven-dried flask and azeotropically dried using toluene. Dichloromethane (16 mL) and carbon tetrabromide (10.81 g, 8.15 mmol) were added and the solution was stirred, cooled to 0° C. and treated with triphenylphosphine (8.5 g, 32.41 mmol). The mixture was stirred for 5 h at 0° C., then methanol (1.8 mL) was added and stirring was continued overnight at room temperature. The mixture was diluted with diethyl ether (80 ml) and the resulting suspension was filtered and washed with diethyl ether (30 ml). The solvents were combined and evaporated under reduced pressure and the crude product was purified by silica gel column chromatography eluting with hexane/ethyl acetate (19:1 to 4:1, v/v) to give the title bromide (4) (1.0 g, 40%) as a colourless oil:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N+:12]([CH:15]=[C:16](SC)[S:17]([CH3:19])=O)([O-:14])=[O:13].C[O-].[Na+]>CO>[CH3:19][S:17][C:16]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:15]=1[N+:12]([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: NCC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CSc1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
α-Aminoacetophenone hydrochloride (6.87 g, 0.040 mol) was mixed with 1-nitro-2-methylthio-2-methylsulphinylethylene (7.25 g, 0.040 mol) in 300 ml dry methanol and warmed at 60°. Sodium methoxide (from 0.92 g sodium, 0.080 g atom) in methanol (25 ml) was added dropwise, with stirring, over about 10 minutes. After addition, the mixture was stirred at 60° for one hour, and then filtered to give 2-methylthio-3-nitro-4-phenylpyrrole 5.66 g, m.p. 259°-261° dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:30])[NH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:30])[N:25]([C@H:11]([CH3:12])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:10])[CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH:26]=[N:27]2)=[CH:22][CH:21]=1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]cnc2cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H](n1cnc2cc(Cl)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C

Procedure:
To a solution of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (2.46 g, 9.8 mmol, obtained as described in Tasaka et al., Chem.Pharm.Bull. 1993, 41, 1035-1042) in N-methylpyrrolidone (10 mL), 7-chloro-3H-quinazolin-4-one (1.77 g, 9.8 mol) and K2CO3 (1.35 g, 9.8 mmol) were added. The resulting solution was heated at 80° C. for 3 days. The mixture was cooled to room temperature, water was then added and the pH was adjusted to 7. The mixture was extracted with ethyl acetate (4×). The combined organic extracts were washed with water (4×), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to a reduced volume and was allowed to crystallize at 0° C. The resulting product was filtered, dried and dissolved in hot ethanol (10 mL/g). The insoluble material was filtered off, and the filtrate was then poured over cold water (120 mL/g of UR-9825) under stirring. The resulting precipitate was filtered and dried in vacuo (50° C.) to give the desired product as a white amorphous powder (3.1 g, 75%).
Reaction SMILES: [H-].[Li+].C([Al+]CC(C)C)C(C)C.[H-].C([O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[O:27][CH2:28][CH3:29])CC.Cl>C1COCC1>[CH2:28]([O:27][C:19]1[C:20]([CH:24]([CH3:25])[CH3:26])=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][OH:16])[CH3:29]
Reactant: CCCOC(=O)c1cccc(C(C)C)c1OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1c(CO)cccc1C(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 104.9 %

Procedure:
Diisobutylaluminum lithium hydride (55.0 mL of a 1.0 M in hexanes, 55.0 mmol) was added drop-wise to an ice-cold solution of 2-ethoxy-3-isopropylbenzoic acid propyl ester (4.34 g, 18.3 mmol) in THF (40 mL). After the addition was complete, the ice bath was removed and reaction mixture was stirred for 18 h. The reaction was cooled to 0° C. and HCl (1N, 275 mL) was added until all the resulting solids returned to solution. The mixture was extracted with EtOAc (3×150 mL). The combined organics were washed with brine (2×200 mL), dried (Na2SO4) and concentrated to yield the title compound (3.73 g, quantitative) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.24 (d, J=5.7 Hz, 1H), 7.16 (d, J=1.7 Hz, 1H), 7.07 (t, J=7.5 Hz, 1H), 5.02 (t, J=5.6 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 3.77 (q, J=7.0 Hz, 2H), 3.32-3.25 (m, 1H), 1.33 (t, J=6.9 Hz, 3H), 1.16 (d, J=6.9, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][C:16]1[N:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])=[CH:24][CH:23]=2)[C:18](=[O:21])[NH:19][N:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:19]1[C:18](=[O:21])[N:17]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]([F:34])([F:35])[CH:31]([F:32])[F:33])=[CH:26][CH:27]=2)[C:16]([CH3:15])=[N:20]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: Cc1n[nH]c(=O)n1-c1ccc(OCC(F)(F)C(F)F)cc1
Product: Cc1nn([C@H](C)[C@@]2(c3ccc(F)cc3F)CO2)c(=O)n1-c1ccc(OCC(F)(F)C(F)F)cc1
Yield: 46.2 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.50 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.61 g of 5-methyl-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.45 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-5-methyl-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]3[O:19][C:13]4=[C:14]([NH2:18])[N:15]=[CH:16][CH:17]=[C:12]4[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[I:20]C1C=NC(N)=C2OC(C3C=CC=C4C=3C=CN=C4)=CC=12>>[S:1]1[C:5]2[C:6]([C:10]3[O:19][C:13]4=[C:14]([NH2:18])[N:15]=[CH:16][C:17]([I:20])=[C:12]4[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Nc1nccc2cc(-c3cccc4ccsc34)oc12
Reactant: Nc1ncc(I)c2cc(-c3cccc4cnccc34)oc12
Product: Nc1ncc(I)c2cc(-c3cccc4ccsc34)oc12
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield from 2-(1-benzothiophen-7-yl)furo[2,3-c]pyridin-7-amine by a procedure analogous to Intermediate 10, Step B. 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, J=7.5 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.95 (d, J=1.5 Hz, 2H), 7.64-7.58 (m, 2H). 7.18 (s, 1H). 6.67 (br s, 2H).
Reaction SMILES: O=[C:2]1[NH:7][N:6]=[C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]2=[CH:3]1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc2c(n[nH]1)-c1ccccc1CCC2
Product: Clc1cc2c(nn1)-c1ccccc1CCC2
Temperature: 25 °C

Procedure:
A mixture of the compound of formula (De), 3-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (4.0 g, 19.3 mmol) and POCl3 (20 mL) was refluxed for 2 h. After cooling to ambient temperature, the volatiles were evaporated. The residue was poured into a mixture of ice water and sodium bicarbonate, CH2Cl2 (200 mL) was added to dissolve the solid. The layers were separated, and the aqueous layer was extracted with CH2Cl2 one more time. The combined organic layers were washed with brine. After being dried (MgSO4), filtered, and concentrated, the compound of formula (Df), 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine was obtained as a yellow solid (4.3 g, 99%), 1H NMR (300 MHz, CDCl3) δ: 7.82 (m, 1H), 7.45-7.24 (m, 4H), 2.59-2.51 (m, 4H), 2.27 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 231 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:16])([F:17])[F:18])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: O=C(NC1=N[C@](CF)(c2cccc(F)c2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@](CF)(c2cccc(F)c2F)C[C@@H](C(F)(F)F)O1
Temperature: 60 °C
Yield: 98.3 %

Procedure:
To a solution of N-((4S,6S)-4-(2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (2.2 g, 5.28 mmol) in MeOH (25 mL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.947 mL, 6.34 mmol) The mixture was heated in a 60° C. oil bath for 22 h. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-40% EtOAc/hexane) to afford (4S,6S)-4-(2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.62 g, 5.19 mmol, 98% yield) as light yellow solid. MS m/z=313.1 [M+H]+. Calculated for C12H10F6N20: 312.2
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:6]=1)[CH3:2].Cl.N1C=CC(CCl)=CC=1.[C:33]([O-])([O-])=[O:34].[K+].[K+].[I-].[K+].CN(C=O)C>O>[CH2:22]([N:3]([CH2:1][CH3:2])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:6]=1[CH:33]=[O:34])[CH3:23]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccncc2)c1
Agent: Cl
Agent: ClCc1ccncc1
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccncc2)c1C=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
A suspension of N,N-diethyl-4-methoxy-3-(4-pyridinylmethoxy)benzamide (19.0 g), 4-picolylchloride hydrochloride (15.0 g), K2CO3 (60.0 g) and potassium iodide (5.0 g) in DMF (500 mol) was stirred at 80° C. for 2 hours and then heated to 150° C. for 15 minutes. After cooling to room temperature, the mixture was poured into 3 l of water, and extracted twice with ethyl acetate. The combined organic phases were washed with 5% Na2CO3, dried (Na2SO4) and concentrated in vacuo. High performance liquid chromatography (silica gel, eluting with 1:1 heptane:ethyl acetate) afforded 6.5 g of the product which was crystallized from heptane/acetone, m.p. 117°-118° C.
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([CH:9]1[CH2:10][O:11][CH:19]([C:18]2[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=2)[O:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(CO)CO
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCC1COC(c2ccc(O)cc2)OC1
Yield: 45.7 %

Procedure:
A mixture of 2-n-octylpropane-1,3-diol (5.64 g, 0.03 m), 4-hydroxybenzaldehyde (3.66 g, 0.03 m), benzene (60 ml) and a catalytic amount of 4-toluenesulfonic acid was azeotropically refluxed until no more water was collected (about 16 hours). The solvent was evaporated and the residue was crystallized from 50% aqueous ethanol to yield p-(5-n-octyl-1,3-dioxan-2-yl)phenol (4 g, 48%) mp 96°-97° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:22])=[C:13]([C:16](=[O:21])[C:17]([O:19][CH3:20])=[O:18])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1.CCO.C(=O)=O.[B]1OC2C(=CC=CC=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:22])=[C:13]([C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1
Reactant: COC(=O)C(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [B]1Oc2ccccc2O1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Temperature: -10 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of methyl 2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate (845 mg, 1.528 mmol) in anhydrous toluene (13 mL) under nitrogen atmosphere was added (R)-CBS (0.382 mL, 0.382 mmol) (1M/toluene) and the mixture was cooled to −35° C. (EtOH/dry ice); catecholborane (4.74 mL, 4.74 mmol) (1M/THF) was slowly added dropwise over 1 h 15 min and then allowed to warm to −10° C. in ˜30 min and stirred at this temperature for 1 h. 2M Na2CO3/water and EtOAc was added and the mixture was stirred at RT for 5 min., diluted with EtOAc and water. The organic phase was washed with 2M Na2CO3, 1M NaOH/water, saturated NH4Cl, brine, dried (Na2SO4), concentrated, and purified by column chromatography to provide (S)-methyl 2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (663 mg, 1.334 mmol, 87% yield) as a yellowish foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.69 (s, 3 H), 3.46 (d, J=2.35 Hz, 1 H), 3.81 (s, 3 H), 5.40-5.62 (m, 2 H), 5.91 (d, J=2.15 Hz, 1 H), 6.41 (d, J=3.52 Hz, 1 H), 6.93-7.20 (m, 4 H); LCMS (m/z) ES+=473 (M+1). Chiral HPLC (Whelk 0 SS 4.6×250 mm column with 25% IPA in hexane. UV was monitored at 215, 254, and 280 nm.): 94% ee.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:28][N:27]=[N:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].[NH3:30]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:30])=[O:16])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:28][N:27]=[N:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:6][CH:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(-c3cnns3)cc2)C[C@@H]1C
Reactant: N
Product: CC(=O)N1c2ccc(C(N)=O)cc2C(Nc2ccc(-c3cnns3)cc2)CC1C

Procedure:
Reactions and treatments were carried out in the same manner as in Example 118, using 61.2 mg of (2S,4R)-1-acetyl-2-methyl-4-{[4-(1,2,3-thiadiazol-5-yl)phen yl]amino}-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 44.9 mg (73.5%, cis:trans=20:1) of the title compound was obtained as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.[CH2:29]([O:31][C:32](=[O:35])[CH:33]=O)[CH3:30].C1(C)C=CC=CC=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:10]2[C:5]([O:4][C:3]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=3[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=2)=[O:12])[CH2:14][CH2:15]1)[CH3:30]
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CCOC(=O)C=O
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 34 %

Procedure:
To [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (200 mg, 0.478 mmol, 1.0 equiv; Example 147) was added a 50% solution of glyoxylic acid ethylester in toluene (1.03 g, 1 mL, 1.913 mmol, 4.0 equiv; [CAS RN 924-44-7]), dibutyltin dichloride (14.6 mg, 0.048 mmol, 0.1 equiv; [CAS RN 683-18-1]) and phenylsilane (103.8 mg, 118 μL, 0.956 mmol, 2.0 equiv; [CAS RN 694-53-1]). The reaction mixture was heated by microwave irradiation to 100° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 82.7 mg (34%) of the title compound as a light yellow solid. MS (ISP): 504.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc3c(N)ncnn23)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(c2cc(Br)c3c(N)ncnn23)C1
Temperature: 25 °C
Yield: 167.4 %

Procedure:
A solution of tert-butyl 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)morpholine-4-carboxylate (840 mg, 2.63 mmol) in DMF (20 mL) was cooled to −40° C. and treated with 1,3-dibromo-5,5-dimethylhydantoin (376 mg, 1.32 mmol). The reaction was warmed to rt over 3 h, and then partitioned between EtOAc and 1N sodium carbonate. The organic layer was separated and washed with water and brine. After drying with sodium sulfate and removal of the solvent in vacuo, trituration with ether provided the desired compound as a brown solid (880 mg, 84%). 1H-NMR (DMSO): δ 7.89 (s, 1H), 4.88 (dd, 1H, J=10, 3 Hz), 3.95 to 4.06 (m, 1H), 3.82 to 3.91 (m, 1H), 3.70 to 3.79 (m, 1H), 3.55 (ddd, 1H, J=11, 11, 3 Hz), 2.92 to 3.28 (m, 2H), 1.37 (s, 9H); MS: LC/MS (+esi): m/z=400.2 [MH]+; LC/MS rt=2.76 min.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(N(CC)CC)C>[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][CH:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]([F:34])([F:33])[F:32])[C:19]5[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=5[C:17]=4[N:16]=3)=[CH:10][CH:9]=2)[CH2:42][CH2:41]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1
Solvent: CCN(CC)CC
Product: CN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccccc3C(F)(F)F)C4)cc2)CC1

Procedure:
This was synthesized by using 4-(6-(2-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-Methylpiperazine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=157-158° C. 1H NMR 400 MHz (DMSO-d6) δ 9.55 (s, 1 H); 8.38-8.34 (m, 2 H), 7.82-7.49 (m, 3 H), 7.58 (t, 1 H), 7.51-7.40 (m, 3 H), 7.27 (d, J=8.4 Hz, 1 H), 7.18-7.15 (m, 2 H), 6.77 (d, J=7.6 Hz, 1 H), 4.64 (t, J=7.6 Hz, 1 H), 3.35 (bs, 2 H), 3.17-3.08 (m, 3 H), 2.69-2.65 (m, 2 H), 2.50-2.31 (m, 7 H), 2.15 (s, 3 H). LCMS 544 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cc4F)ccn3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 65.9 %

Procedure:
4-(2-Fluoro-4-nitrophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (138 mg) was dissolved in tetrahydrofuran (30 ml). After adding 20% palladium hydroxide-carbon (89 mg), the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated under reduced pressure, and the resultant residue was dried under reduced pressure to provide the title compound (85 mg, 66%) as pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12].[C:18](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=2[CH3:12])=[C:2]([CH3:18])[CH:3]=[N:4]1
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2c(C)cnn2C)c(C)s1
Yield: 72.1 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (420 mg, 1.33 mmol), potassium carbonate (921 mg, 6.66 mmol), PdCl2(dppf) (98 mg, 0.13 mmol) and trimethylboroxine (0.371 ml, 2.67 mmol) in N,N-dimethylformamide (6.663 ml) was stirred at 110° C. in a sealed tube for 2 h. This reaction was run in two batches (100 mg and 420 mg) which were combined and partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (240 mg, 58%) as a yellow oil: LCMS (ES) m/e 251 (M+H)+.