Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].[ClH:16]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([CH3:14])[CH2:6][C:7]([OH:9])=[O:8].[ClH:16]
Reactant: CN(C)CCN(C)CC(=O)OC(C)(C)C
Agent: Cl
Product: CN(C)CCN(C)CC(=O)O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
tert-Butyl 2-[[2-(dimethylamino)ethyl] (methyl)amino]acetate (1.25 g) prepared in Step A was added with 4 N hydrogen chloride (solution in 1,4-dioxane, 15 ml), and the mixture was stirred at 60° C. for 6 hours. The reaction mixture was cooled to room temperature, and the deposited solids were taken by filtration, washed with diethyl ether, and then dried under reduced pressure to obtain the title compound as hydrochloride (886 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][S:7]2.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br.Cl>C(Cl)Cl>[Br:18][C:11]1[C:2]([CH3:1])=[C:3]2[C:8](=[C:9]([CH3:12])[CH:10]=1)[S:7][CH2:6][CH2:5][C:4]2=[O:13]
Reactant: BrBr
Reactant: Cc1ccc(C)c2c1SCCC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c2c1SCCC2=O
Reaction time: 0.25 h

Procedure:
66.5 g (0.35 mol) of 5,8-dimethyl-4-thiochromanone, together with 118 g (0.87 mol) of aluminum chloride, were dissolved or suspended in 600 ml of methylene chloride. After 15 min of stirring, 62.2 g (0.39 mol) of bromine were slowly added dropwise, and the reaction mixture was subsequently boiled under reflux for 10 min. The reaction mixture, which was still warm, was poured into 220 ml of conc. hydrochloric acid in crushed ice. The mixture was stirred for 10 min, the methylene chloride phase was separated off and the aqueous phase was extracted with diethyl ether (3×400 ml). The combined organic phases were washed with water, dried over MgSO4 and concentrated using a rotary evaporator.
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1.C([O-])(=O)C.[NH4+].I([O-])(=O)(=O)=O.[Na+].O>CC(C)=O.C1(C)C=CC=CC=1>[C:22]([O:21][C:20]([NH:19][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([B:4]([OH:5])[OH:3])=[CH:14][CH:13]=2)[CH2:18][CH2:17][CH2:16]1)=[O:26])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(B(O)O)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a solution of tert-butyl {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate [Int-1B] (5.63 g, 20.0 mmol, 1 eq) in 191 mL acetone is added ammonium acetate (7.38 g, 95.6 mmol, 4.78 eq). After the addition of sodium periodate (13.6 g, 63.6 mmol, 3.15 eq) the reaction mixture was stirred overnight at rt. Then, the white suspension was treated with water. The remaining solid was isolated by filtration and treated with toluene that was directly removed by a rotary evaporator. This procedure was repeated three times. The remaining solid was dried in vacuo at 60° C. overnight to give 3.87 g (75%) of the title compound in 85% purity (UPLC, area-%).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([C:33]([OH:35])=O)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31].O[NH:37]/[C:38](=[N:55]\[H])/[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:42]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:33]2[O:35][N:55]=[C:38]([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[NH:44][C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:42]4)[N:37]=2)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:31])[CH3:32]
Reactant: [H]/N=C(\NO)c1ccc2[nH]c(CCC(=O)OCC)cc2c1
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Temperature: 120 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
EDCI (92 mg) and HOBT (80 mg) were added to a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (52 mg) in THF (6 mL). The resulting mixture was stirred for 1 hour followed by addition of ethyl 3-{5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D31) (100 mg). The resulting mixture was stirred for 3 hours followed by addition of TBAF (251 mg). The reaction vessel was sealed, and heated at 120° C. in the microwave for 3 hours. THF was removed. The residue was dissolved in EtOAc. The organic solution was washed with saturated aqueous sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D115) (54 mg). MS (ES): C23H23ClN4O4 requires 454; found 455.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2[C:41]([N:46]([CH3:48])C)=[CH:42][CH:43]=CC=2)CCCCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.N1CCCC1>[Cl-].[NH4+].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]>[CH2:17]([O:16][C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][C:2]([N:46]4[CH2:41][CH2:42][CH2:43][CH2:48]4)=[CH:15][CH:14]=3)[C@@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:6]=2[CH:7]=1)[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCNC1
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(N3CCCC3)ccc1O2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A vial was charged with (R)-2′-bromo-7′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (0.100 g, 0.240 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (1.132 mg, 2.88 μmol), Pd2(dba)3 (1.097 mg, 1.198 μmol), LiHMDS (1.0 M in THF) (0.959 mL, 0.959 mmol), and pyrrolidine (0.059 mL, 0.719 mmol). The vial was sealed and heated to 100° C. overnight. Additional Pd2(dba)3 (1.097 mg, 1.198 μmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (1.132 mg, 2.88 μmol), LiHMDS (1.0 M in THF) (0.480 mL, 0.480 mmol) and pyrrolidine (0.059 mL, 0.719 mmol) were added and the reaction was at 100° C. for 2 hours. The reaction mixture was diluted with a saturated aqueous ammonium chloride solution (10 mL) and extracted three times with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The material was purified via Gilson HPLC (20-90% MeCN:H2O). The product fractions were partitioned between DCM and saturated sodium bicarbonate solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford (S)-2′-(neopentyloxy)-7′-(pyrolidin-1-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:35]C3C=CC([N+]([O-])=O)=CC=3)[C:22]2=[O:45])[CH2:17][CH2:16]1.Br.[CH2:47](C1C(N2C(=O)C3C(=CC=C([N+]([O-])=O)C=3)N(C)C2=O)CCNC1)[CH3:48]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH3:35])[C:22]2=[O:45])[CH:19]([CH2:47][CH3:48])[CH2:20]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(Cc5ccc([N+](=O)[O-])cc5)c4=O)CC3)c2cc1OC
Reactant: CCC1CNCCC1n1c(=O)c2cc([N+](=O)[O-])ccc2n(C)c1=O
Agent: Br
Product: CCC1CN(c2ncnc3cc(OC)c(OC)cc23)CCC1n1c(=O)c2cc([N+](=O)[O-])ccc2n(C)c1=O
Yield: 39 %

Procedure:
The procedure similar to that described in Example 15 was repeated, except that 61.1 mg (0.15 mmol) of 3-(1-exthoxycarbonyl-3-ethyl-4-piperidinyl)-1,2,3,4 -tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline (Compound 11: diastereomixture) was used in place of Compound a, whereby 70.4 mg of crude 3-(3-ethyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline hydrobromide was obtained. The product was treated in the similar manner as in Example 15 to give 30.4 mg (yield: 39%) of Compound 104 as a 6:4 diastereomixture.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.Cl.[OH:21][C:22]1[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([CH3:32])[C:22]=4[OH:21])[CH2:27]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2cccnc2)nc2ccccc12
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccnc3)nc3ccccc13)C2
Yield: 13 %

Procedure:
Reaction of 2-(3-pyridinyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 88 (13% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.13 and 2.17 (2s, 3H), 2.66 and 2.92 (2t, 2H), 3.52 and 4.05 (2t, 2H), 4.43 and 4.94 (2s, 2H), 6.30 and 6.75 (2d, 1H), 6.80 and 7.00 (2d, 1H), 7.61-8.23 (m, 5H), 8.39-8.45 (2s, 1H), 8.75-8.83 (m, 2H), 9.60 and 9.65 (2s, 1H); MS (ESI) m/z 397 ([M+H]+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]=[S:8]1(=[O:32])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:28])[C:26]#[N:27])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:29][CH2:30][CH2:31][CH:10]2[NH:9]1.[H-].[Na+].[Cl-]>C1COCC1>[O:32]=[S:8]1(=[O:7])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:28])[CH2:26][NH2:27])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:29][CH2:30][CH2:31][CH:10]2[NH:9]1
Reactant: CC(C#N)c1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(CN)c1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Reaction time: 3 h

Procedure:
200 mg (5.25 mmol) of LiAlH4, in small portions, are added to a solution containing 485 mg (1.31 mmol) of the compound of Step A above in 15 ml of THF. After reacting for 3 hours, the excess hydride is hydrolysed by dropwise addition of saturated aqueous NaCl solution. The reaction mixture is filtered, the solid is rinsed several times with THF and the filtrate is evaporated to yield a white meringue corresponding to the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@@H:17]2[C@@H:13](OC(=S)O2)[C@H:12]([N:19]2[C:23]3[N:24]=[CH:25][N:26]=[C:27]([NH:28][C@@H:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31][CH2:30]4)[C:22]=3[CH:21]=[CH:20]2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCN(C)P1C1C=CC=CC=1>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:11][C@@H:12]([N:19]2[C:23]3[N:24]=[CH:25][N:26]=[C:27]([NH:28][C@@H:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31][CH2:30]4)[C:22]=3[CH:21]=[CH:20]2)[CH:13]=[CH:17]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@@H]2OC(=S)O[C@H]12
Agent: CN1CCN(C)P1c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C=C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of (3aR,4S,6R,6aS)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}tetrahydro-3aH-cyclopenta[d][1,3]dioxole-2-thione (138 mg, 0.257 mmol) in THF (0.860 mL) at 0° C. under an atmosphere of nitrogen was added 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (0.147 mL, 0.793 mmol) dropwise. The solution was stirred for 10 min at 0° C. and then at rt for 5 h. The solvent was removed and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in hexanes to afford the title compound as a clear oil (˜70% purity, 81.9 mg, 48%). LC/MS: Rt=2.10 min, ES+ 462 (FA standard).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:30][OH:31])=[C:19]([N:23]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:34])C.O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:30][OH:31])=[C:19]([N:23]3[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[O:34])=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4ccc(C#N)n4)c3CO)ncc2c1
Reactant: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4ccc(C(N)=O)n4)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
In a 10 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrazole-3-carbonitrile (16 mg, 38.3 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (1 mg, 2.33 μmol, Eq: 0.0608) were combined with ethanol (821 μl) and water (410 μl) to give a colorless solution. The reaction mixture was heated to 80° C. and stirred for 2 h. The reaction mixture was diluted with DCM. The reaction mixture was filtered through glass fiber paper. The crude material was purified by preparative HPLC to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-3-carboxylic acid amide (11 mg, 66%, [M+H]+ 436) of lyophilized white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[CH2:53]([O:60][C:61]([N:63]1[C:68]2[CH:69]=[C:70]([Cl:74])[CH:71]=[C:72](Br)[C:67]=2[O:66][CH2:65][CH2:64]1)=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.[C:75]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][CH2:83]1)=[O:81])([CH3:78])([CH3:77])[CH3:76]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[CH2:53]([O:60][C:61]([N:63]1[C:68]2[CH:69]=[C:70]([Cl:74])[CH:71]=[C:72]([N:85]3[CH2:84][CH2:83][N:82]([C:80]([O:79][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:81])[CH2:87][CH2:86]3)[C:67]=2[O:66][CH2:65][CH2:64]1)=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(OCc1ccccc1)N1CCOc2c(Br)cc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc3c2OCCN3C(=O)OCc2ccccc2)CC1
Temperature: 95 °C
Reaction time: 12 h

Procedure:
A three neck flask was charge with tris(dibenzylideneacetone)dipalladium(0) (21.5 mg, 0.024 mmol, 2 mol % Pd), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (36.4 mg, 0.059 mmol, 5 mol %) and sodium-tert-butoxide (159 mg, 1.65 mmol) and flushed with nitrogen. A solution of 8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester (450 mmg, 1.18 mmol) and piperazine-1-carboxylic acid tert-butyl ester (263 mg, 1.41 mmol) in toluene (2 mL) was added. The mixture was heated to 95° C. and was stirred for 12 hours. The mixture was cooled to room temperature, taken up in ethyl acetate, filtered through celite and concentrated. The crude material was purified by flash chromatography on silica gel (eluting with hexane-ethyl acetate; 7:3, v/v) to give 8-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester a colorless oil (275 mg, 48%). MS: MH+=488.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32].C(O)C(N)(CO)CO>ClCCCl>[CH3:1][C:2]1[C:7]([NH:8][C:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:32])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)c1cccs1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.4 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of thiophene-2-carbonyl chloride (40 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 7.8 mg of the title compound.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@@H:18]2[C:23](O)=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O.C(Cl)(Cl)Cl.CO>[C:1]([NH:4][NH:5][C:23]([C@H:18]1[CH2:17][CH2:16][C@@H:15]2[CH2:22][N:19]1[C:20](=[O:21])[N:14]2[O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: O=C(O)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 14 h
Yield: 36.6 %

Procedure:
To a mixture of acetic acid hydrazide (1.47 gm, 19.9 mmol) and trans-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (5 gm, 18.1 mmol) in N,N-dimethyl formamide (50 ml), was added EDC hydrochloride (5.19 gm, 27.1 mmol), DIPEA (9.50 ml, 54.3 mmol) and HOBt (3.66 gm, 27.1 mmol). The reaction mixture was stirred at a temperature between 25° C. to 35° C. for 14 hours. It was diluted with water (250 ml) and extracted with ethyl acetate (75 ml×3). The combined organic extract was washed with water, saturated aqueous sodium chloride solution (100 ml) and layers were separated. The organic layer was concentrated in vacuum to provide the crude compound, which was subjected for silica gel column chromatography using methanol chloroform to provide Step-1 product (2.2 gm) in 33% yield as powder.
Reaction SMILES: [NH2:1][OH:2].CC1CCCO1.[Na+].[Cl-].[C:11](#[N:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:11](=[N:1][OH:2])([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1
Reactant: NO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: NC(=NO)c1ccccc1
Temperature: 70 °C

Procedure:
Benzonitrile (50.0 g, 0.485 mol) was added to a 250 mL flask and heated to 70° C. with stirring. Deionized water (1.0 g) was added and the temperature was lined out at 70° C. Aqueous hydroxylamine (50%, 37.50 g, 34.8 ml, assay was 53.3%, 0.605 moles) was added via a syringe pump over 1.5 hours while maintaining the temperature at 70°±2° C. HPLC analysis indicated that the conversion of benzonitrile was >99% after about 2.5 hours of reaction time. The batch was heated for a total of 3.5 hours at 70° C., then was cooled to 60° C. The batch was transferred to a 500 mL flask with 2-methyltetrahydrofuran (208.98 g), followed by 20 wt % aqueous NaCl (40.0 g). The mixture was heated to 60° C., and the phases were separated at 60° C. to give a solution of benzamide oxime in 2-methyltetrahydrofuran (281.80 g) and aqueous waste (44.61 g). The 2-methyltetrahydrofuran solution assayed for 21.73 wt % benzamide oxime.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[C:38]([NH:40][C:41]3[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=3)[C:37]3=[C:53]([CH3:57])[N:54]=[C:55]([CH3:56])[N:36]3[N:35]=2)=[CH:30][CH:29]=1>>[CH3:57][C:53]1[N:54]=[C:55]([CH3:56])[N:36]2[C:37]=1[C:38]([NH:40][C:41]1[CH:42]=[C:43]([O:51][CH3:52])[C:44]([O:49][CH3:50])=[C:45]([O:47][CH3:48])[CH:46]=1)=[N:39][C:34]([C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:1](=[O:5])[CH2:2][CH3:3])=[CH:33][CH:32]=1)=[N:35]2
Reactant: CCC(=O)O
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCC(=O)Nc1ccc(-c2nc(Nc3cc(OC)c(OC)c(OC)c3)c3c(C)nc(C)n3n2)cc1

Procedure:
13 mg (0.17 mmol) of propionic acid, 23 mg (0.17 mmol) of HOBt, 47 mg (0.46 mmol) of 4-methylmorpholine, 33 mg (0.17 mmol) of EDC and 65 mg (0.21 mmol) of N-[2-(4-aminophenyl)-5,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 are reacted analogously to example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[N:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:32]4[CH:33]=[CH:34][O:30][N:31]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccon1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccon2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and isoxazole-3-carboxylic acid (17 mg, 0.15 mmol).
Reaction SMILES: [I-].C[N+]([CH2:6][C:7]1[N:8]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][CH:11]=1)(C)C.CN1CCN(C)C1=O>ClCCl>[CH3:6][C:7]1[N:8]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(-n2cccc2C[N+](C)(C)C)c1
Agent: [I-]
Solvent: ClCCl
Solvent: CN1CCN(C)C1=O
Product: COC(=O)c1cccc(-n2cccc2C)c1
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To the mixture of methyl 3-(2-trimethylammoniomethyl-pyrrol-1-yl)benzoate iodide (2.0 g) and 1,3-dimethyl-imidazolidin-2-one (6 ml) was added borane-pyridine complex (1.1 ml) and the mixture was stirred for 1.5 hours at 105° C. To the mixture was added dichloromethane, and the mixture was washed with water, 1N-hydrochloric acid and water successively. The mixture was dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(2-methylpyrrol-1-yl)benzoate (1.01 g) as an oil.