Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:9]=[C:10]2[CH:16]=[C:15]([C:17](O)=[O:18])[N:14](S(C3C=CC=CC=3)(=O)=O)[C:11]2=[N:12][CH:13]=1.CN.[CH3:36][N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:8]2[N:9]=[C:10]3[CH:16]=[C:15]([C:17]([NH:37][CH3:36])=[O:18])[NH:14][C:11]3=[N:12][CH:13]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1
Reactant: COc1cc(CCc2cnc3c(cc(C(=O)O)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2nc(CCc3cc(OC)cc(OC)c3)cnc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a stirred solution of 2-(3,5-dimethoxyphenethyl)-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine-6-carboxylic acid (27 mg, 57.8 μmol) in N,N-dimethylformamide (2 mL), methylamine (2.0 M in THF, 57.8 μL, 0.116 mmol), HATU (43.9 mg, 0.116 mmol) and N,N-diisopropylethylamine (40.2 μL, 0.231 mmol) were added sequentially at ambient temperature. After 1 hour, the reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was dissolved in methanol (2.0 mL), and potassium carbonate (16.0 mg, 0.116 mmol) was added. The reaction mixture was then warmed up to 60° C. After 1 hour, the crude mixture was allowed to warm to room temperature and was then purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at a flow rate of 30 mL/min) to give the desired product (6.0 mg, 30%) as its TFA salt. LCMS calculated for C18H21N4O3 (M+H)+: m/z=341.2. Found: 341.1.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:73][O:74][C:75]1[CH:80]=[CH:79][C:78]([CH2:81][SH:82])=[CH:77][CH:76]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:4]1[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:11]=[C:2]([S:82][CH2:81][C:78]2[CH:79]=[CH:80][C:75]([O:74][CH3:73])=[CH:76][CH:77]=2)[C:3]=1[F:21])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COc1ccc(CS)cc1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (22.84 g, 60.65 mmol) in anhydrous 1,4-dioxane (200 mL) was added N,N-diisopropylethylamine (15.68 g, 121.30 mmol). Then Pd2(dba)3 (2.78 g, 3.03 mmol) followed by Xantphos (3.51 g, 6.06 mmol) and 4-methoxy-α-toluenethiol (10.27 g, 66.72 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere and then allowed to warm to ambient temperature. The insoluble matter was filtered off and the filter cake was washed ethyl acetate. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellow solid, 24.18 g, 88.6% yield). 1H NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 7.77 (dd, 1H), 7.41 (dd, 1H), 7.24 (m, 3H), 7.19 (m, 1H), 7.01 (m, 1H), 6.88 (m, 2H), 4.02 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:10]12[CH2:15][CH:14]1[C:13](=[O:16])[O:12][C:11]2=O>>[CH2:1]([N:9]1[C:11](=[O:12])[CH:10]2[CH:14]([CH2:15]2)[C:13]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: O=C1OC(=O)C2CC12
Product: CCCCCCCCN1C(=O)C2CC2C1=O
Temperature: 180 °C

Procedure:
A mixture of n-octylamine (24.2 g) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (20.0 g) was heated at 180° C. for 2.5 hours and was then cooled to room temperature. The mixture was distilled in vacuo (boiling point 140-142° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: Cl.Cl[C:3]1C=CC(NN)=CC=1.BrCCN1CCN(C(OC(C)(C)C)=O)CC1.C(OC(OCC)CCCNC)C.[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][N:54](C(OC(C)(C)C)=O)[CH2:53][CH2:52]1)[CH:44]=[C:43]2[CH2:64][CH2:65][NH:66][CH3:67].C=O.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.ClCCl>C(#N)C.C(N(CC)CC)C>[Cl:39][C:40]1[CH:48]=[C:47]2[C:46](=[CH:42][CH:41]=1)[N:45]([CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[C:44]1[CH2:3][N:66]([CH3:67])[CH2:65][CH2:64][C:43]2=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CNCCc1cn(CCN2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc12
Agent: C=O
Agent: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Agent: CCOC(CCCNC)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: CN1CCc2c(n(CCN3CCNCC3)c3ccc(Cl)cc23)C1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate, and triethylamine (General Method 1), N-Boc-1-(4-chlorophenyl)-1-(2-(piperazin-1-yl)ethyl)hydrazine and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3), tert-butyl 4-(2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)ethyl)piperazine-1-carboxylate, formaldehyde and TFA in acetonitrile (General Method 4), and Boc deprotection by using TFA/dichloromethane.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=[C:61]3C=2N=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3[CH:83]=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.CN(C)[C@@H]1CCNC1>>[CH3:61][N:60]([CH3:59])[C@@H:74]1[CH2:78][CH2:77][N:79]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:3]=2)[CH2:83]1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Agent: CN(C)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (BA6) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) replacing 1-(2-amino-ethyl)piperidine with (3R)-(+)-3-(dimethylamino)pyrrolidine. After purification, the compound is partitioned between DCM and saturated NaHCO3(aq). The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 624 (MH+).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:10]=2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Yield: 52.6 %

Procedure:
The nitrile 28A (4.7 g, 12 mmol) dissolved in 50 ml of diethyl ether was added dropwise to a mixture of LiAlH4 (912 mg, 2 equiv.) in diethyl ether (80 mL) stirred at 0° C. Then the mixture was stirred at room temperature overnight. The excess of LiAlH4 was destroyed by water addition at 0° C., the solid formed was filtered, washed with Et2O and the filtrate was dried over Na2SO4 and evaporated to dryness to obtain 2.5 g of the amine 29A as yellow solid. Yield=52% 1HNMR (DMSO, 400 MHz) δ 2.25 (2H, bs), 3.90 (2H, s), 7.90 (4H, d, J=8 Hz), 8.11 (2H, s), 8.40 (4H, d, J=8 Hz)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
A suspension of 4-chloro-6,7-dimethoxyquinoline (1566 mg, 7.00 mmol), 4-aminophenol (917 mg, 8.40 mmol) and cesium carbonate (4561 mg, 14.0 mmol) in dimethyl sulfoxide (14 ml) was stirred at 100° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate/tetrahydrofuran (=1/1). The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate/methanol=60/40). Ethyl acetate was added to the obtained residue and the mixture was filtrated to give the title compound (1267 mg, 61%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28]C(OCC4C=CC=CC=4)=O)[CH:23]=3)[CH:14]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O=[Si]=O>CO.[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=3)[CH:14]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN1Cc2cc(Oc3cccc(NC(=O)OCc4ccccc4)c3)ccc2N=C1NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=[Si]=O
Solvent: CO
Product: CCCN1Cc2cc(Oc3cccc(N)c3)ccc2N=C1NC(=O)OC(C)(C)C

Procedure:
A mixture of [6-(3-benzyloxycarbonylamino-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acid tert-butyl ester (0.008 mol) in methanol (150 mL) was hydrogenated with 10% Pd/C (1 g) as a catalyst. After uptake of H2 gas (1 equiv.), the reaction mixture was filtered over Dicalite and the filtrate was evaporated. The residue was stirred in diisopropyl ether and the resulting precipitate was filtered off and dried to yield the title compound as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[OH:5][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25]([CH:27]3[CH2:28][CH2:29]3)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O[C@H](CCCl)c1ccccc1
Product: O=C(Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1)C1CC1

Procedure:
Prepared by Procedure G and Scheme B1 using (1R)-3-chloro-1-phenyl-1-propanol and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 379.2 (M+H)+.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][N:12]1[C:17](=[O:18])[C:16]2[N:19]=[CH:20][N:21]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH:14]=[N:13]1.[Cl:41]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1>[Cl:41][C:20]1[N:21]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:15]2[CH:14]=[N:13][N:12]([CH3:11])[C:17](=[O:18])[C:16]=2[N:19]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cn1ncc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncc2c(nc(Cl)n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
220 ml of lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution) was added to a 4-L tetrahydrofuran solution of 68.3 g of 5-methyl-1-trityl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one at −75° C. under a nitrogen atmosphere, and the mixture was stirred at −75° C. for 1 hour. Then, 200 ml of a tetrahydrofuran solution of 82.3 g of hexachloroethane was added to the solution. The mixture was allowed to warm to −20° C. 5 L of 5% aqueous ammonium chloride was added, and the mixture was extracted with 4 L of ethyl acetate. The organic layer was washed successively with 5 L of water and 5 L of a saturated sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was suspended in 150 ml of t-butyl methyl ether, and then collected by filtration. The solid was washed twice with 100 ml of t-butyl methyl ether to give 69.7 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][NH:11][C:10]=2[N:9]=1.[ClH:19]>>[ClH:19].[N:9]1[C:10]2[NH:11][CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=[CH:17][C:8]=1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:18])=[O:2]
Reactant: COC(=O)CCCCc1ccc2c(n1)NCCC2
Agent: Cl
Product: O=C(O)CCCCc1ccc2c(n1)NCCC2
Temperature: 50 °C

Procedure:
A mixture of 1-5 (620 mg, 2.50 mmol) and 6N HCl (12 mL) was heated at 50° C. for 18 h. Evaporative removal of the solvent gave 1-6 as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=4)[C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13]3)[CH2:4][CH2:3]1.O.O.[Sn](Cl)Cl>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]4[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=4)[C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13]3)[CH2:4][CH2:3]1
Reactant: CN1CCC(OC2c3cccc(-c4cccc([N+](=O)[O-])c4)c3CCn3cc(-c4ccccc4)nc32)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CN1CCC(OC2c3cccc(-c4cccc(N)c4)c3CCn3cc(-c4ccccc4)nc32)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(1-methylpiperidin-4-yloxy)-8-(3-nitrophenyl)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 242 B) (0.6 mmole), tin(II) chloride dihydrate (2.83 g) in ethanol (15 mL) is refluxed for 2 hours. The mixture is then cooled to room temperature and extracted twice with chloroform. Pooled organic extracts are dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 14% (B) to 24% (B) in 10 minutes) to afford 3-[4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-8-yl]-phenylamine melting at 120° C.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[O:12])[C@H:5]([C:8](=[O:11])[O:9][CH3:10])[NH:6][CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:46]([O:50][C:51]([N:53]([CH3:69])[C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][C:63]([C:66](O)=[O:67])=[CH:62][CH:61]=2)=[CH:56][CH:55]=1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>O.C(OCC)(=O)C.CN(C=O)C>[C:46]([O:50][C:51]([N:53]([CH3:69])[C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][C:63]([C:66]([N:6]([CH:5]([C:4]([NH:3][CH3:2])=[O:12])[C:8]([O:9][CH3:10])=[O:11])[CH3:7])=[O:67])=[CH:62][CH:61]=2)=[CH:56][CH:55]=1)=[O:52])([CH3:47])([CH3:48])[CH3:49]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CNC(=O)[C@@H](NC)C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(N(C)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
N,N2,O-trimethyl-3-oxoserinamide hydrochloride (Intermediate 5-2, 90 mg), HATU (0.17 g) and DIPEA (0.16 mL) were added to a DMF (2.0 mL) solution of 4′-((t-butoxycarbonyl)(methyl)amino)biphenyl-4-carboxylic acid (0.10 g), as obtained in Example 2-(2), and the mixture was stirred for 16 hours at room temperature. Ethyl acetate and water were added to the reaction mixture to isolate the organic layer, and the extract was washed sequentially with water and brine. The system was dried over anhydrous sodium sulfate and, after separation of the desiccant by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3) to obtain 4-((t-butoxycarbonyl)(methyl)amino)-4′-(((2-methoxy-1-((methylamino)carbonyl)-2-oxoethyl)(methyl)amino)carbonyl)biphenyl (white foam) (73 mg, 51%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.[Br:22][C:23]1[C:24]([Si:35]([CH3:38])([CH3:37])[CH3:36])=[C:25]([F:34])[C:26]([F:33])=[C:27]([CH:32]=1)C(OC)=O>C1COCC1.Cl>[Br:22][C:23]1[C:24]([Si:35]([CH3:38])([CH3:37])[CH3:36])=[C:25]([F:34])[C:26]([F:33])=[C:27]([C:19](=[O:21])[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=2)[CH:32]=1
Reactant: COC(=O)c1cc(Br)c([Si](C)(C)C)c(F)c1F
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(Br)cc(C(=O)Cc2ccc(Cl)cc2)c(F)c1F
Reaction time: 0.08 h

Procedure:
To a solution of NaHMDS (1.0 M in THF, 7.7 mL, 7.7 mmol) in anhydrous THF (25 mL) at −78° C. was added a solution of 4-chlorophenylacetic acid (0.528 g, 3.09 mmol) in anhydrous THF (25 mL) over 10 minutes. The solution was stirred for 5 minutes, then a solution of the product of Step C (4.16 g, 7.8 mmol) in THF (25 mL) was added drop wise over 10 minutes. The mixture was stirred at −78° C. for two hours. The mixture was diluted with 2N HCl (aq, 50 mL), then the product was extracted into EtOAc. The organics were dried over Na2SO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% toluene/hexanes to afford the title compound. 1H NMR (600 MHz, CDCl3): δ 7.74 (dd, J=5.3, 1.8 Hz, 1H); 7.31 (d, J=8.2 Hz, 2H); 7.16 (d, J=8.5 Hz, 2H); 4.22 (s, 2H); 0.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]([CH:24]([CH3:26])[CH3:25])=[CH:19][C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH:24]([CH3:26])[CH3:25])[N:17]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C=C(N)C(C)C
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Solvent: CC#N
Product: COC(=O)c1c(C(F)(F)F)cc(-c2ccc(Cl)cc2)nc1C(C)C

Procedure:
150 mg (0.599 mmol) of 1-(4-chlorophenyl)-4,4,4-trifluorobutane-1,3-dione [Katsuyama et al., Synthesis, 1321-1324 (1997)] and 171 mg (1.20 mmol) of methyl 3-amino-4-methylpent-2-enoate [Holz et al., J. Org. Chem. 68., 1701-1707 (2003)] in 2 ml of acetonitrile were reacted at reflux temperature overnight. The volatile components were then removed on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10). This gave 34 mg (16% of theory) of the target compound.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[C:71]([Cl:73])[CH:70]=[CH:69][N:68]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:73][C:71]1[CH:70]=[CH:69][N:68]=[C:67]([C:57]2[C:56]([CH3:74])=[C:55]([NH:47][C:46]3[C:41]([N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[N:42][CH:43]=[C:44]([N:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)[CH:45]=3)[C:64]3[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=3[F:65])[N:58]=2)[CH:72]=1
Reactant: Cc1c(-c2cc(Cl)ccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(Cl)ccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.021 g, 0.044 mmol), 2,5-dimorpholinopyridin-3-amine (0.088 g, 0.33 mmol), 4-chloro-2-(4-chloropyridin-2-yl)-5,7-difluoro-3-methylquinoline (0.090 g, 0.28 mmol), Pd2dba3 (10.14 mg, 0.011 mmol) and sodium tert-butoxide (0.067 g, 0.69 mmol) in toluene (2.8 mL) at 120° C. for 28 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 2-(4-chloropyridin-2-yl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.59 (1H, d, J=5.3 Hz), 7.98 (1H, d, J=0.6 Hz), 7.78 (1H, br. d, J=11.9 Hz), 7.64 (1H, d, J=2.5 Hz), 7.62 (1H, m), 7.40 (1H, dd, J=5.4, 2.1 Hz), 7.03 (2H, ddd, J=13.3, 8.61, 2.4 Hz), 6.44 (1H, br s), 3.93 (4H, br. s.), 3.82 (4H, app t, J=4.8 Hz), 3.25 (4H, br. s), 3.08 (4H, app t., J=4.8 Hz), 2.22 (3H, s). Mass Spectrum (ESI) m/e=553.2 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][NH:15][CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1.[CH3:19][C:20]([CH3:22])=O.[BH4-].[Na+].Cl>CO.CCOCC.O1CCOCC1>[ClH:2].[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][N:15]([CH:20]([CH3:22])[CH3:19])[CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1
Reactant: CC(C)=O
Reactant: CCc1cc(Cl)c2c(c1)[C@H]1CNC[C@@H]1NC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCc1cc(Cl)c2c(c1)[C@H]1CN(C(C)C)C[C@@H]1NC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 119.6 %

Procedure:
To a solution of (3aR,9bS)-6-chloro-8-ethyl-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one hydrochloride (Example 29) (19 mg, 0.066 mmol) in 2 mL of methanol was added acetone (0.015 mL, 0.20 mmol) followed by sodium borohydride (13 mg, 0.33 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 18 h. The reaction was concentrated and the residue was purified (ISCO, elution with 0-15% methanol/methylene chloride) to afford the free base. To the free base in 1 mL of ether was added 4N HCl in dioxane (0.05 mL). The mixture was concentrated in vacuo, triturated with ether, and dried in vacuo to afford 13 mg (60%) of the title compound of Example 64 as a white solid. 1H NMR (CD3OD): 7.36 (s, 1H), 7.07 and 7.02 (s, 1H), 4.27-4.21 and 4.16-4.11 (m, 1H), 3.88-3.35 (overlapping m, 6H), 2.70 (q, 2H), 1.48-1.42 (m, 6H), 1.26 (t, 3H). LRMS (ESI): 293.3/295.3 (M+H)+.