Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:39](Cl)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:29]1([C:39]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](OC(=O)c3cccc4ccccc34)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Into a 25-mL RB-flask was added N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 1-naphthalenecarbonyl chloride (100 mg), diisopropylethylamine (0.30 mL) in THF (0.50 mL) at room temperature. After stirring for 16 hrs at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.70 mg, 71.3% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.90 (d, 1H, J=8.9 Hz), 8.28 (apparent dd, 1H, J=1.5, 7.2 Hz), 8.03 (d, 1H, J=8.7 Hz), 7.88 (dm, 2H, J=8.7 Hz), 7.60-7.48 (m, 7H), 7.40-7.32 (m, 3H), 7.25 (m, 1H), 6.90 (apparent d, 1H, J=7.4 Hz), 6.18 (apparent dd, 1H, J=5.7, 7.8 Hz), 3.42 (m, 2H), 2.84 (m, 2H), 2.53 (m, 2H), 2.44 (apparent sept, partially hidden, 4H, J=7.5 Hz), 2.30-2.10 (m, 2H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 535.6 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:26]4[CH:25]=[CH:24][C:23]([CH3:27])=[C:22]([NH2:28])[C:21]=4[CH:20]=[CH:19][N:18]=3)=[CH:12][C:11]=2[C:29]([F:32])([F:31])[F:30])[CH2:5][CH2:4]1)[CH3:2].[CH:33]1([NH:36][C:37]2[C:38]3[S:45][CH:44]=[C:43]([C:46](O)=[O:47])[C:39]=3[N:40]=[CH:41][N:42]=2)[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:37]2[C:38]3[S:45][CH:44]=[C:43]([C:46]([NH:28][C:22]4[C:23]([CH3:27])=[CH:24][CH:25]=[C:26]5[C:21]=4[CH:20]=[CH:19][N:18]=[C:17]5[NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][N:6]5[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]5)=[C:11]([C:29]([F:31])([F:30])[F:32])[CH:12]=4)=[O:47])[C:39]=3[N:40]=[CH:41][N:42]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)c1csc2c(NC3CC3)ncnc12
Reactant: CCN1CCN(Cc2ccc(Nc3nccc4c(N)c(C)ccc34)cc2C(F)(F)F)CC1
Product: CCN1CCN(Cc2ccc(Nc3nccc4c(NC(=O)c5csc6c(NC7CC7)ncnc56)c(C)ccc34)cc2C(F)(F)F)CC1
Yield: 50.4 %

Procedure:
The procedures of <Step 3> of Example 1 were repeated in sequence, except for using N1-(4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl)-6-methyl-isoquinolin-1,5-diamine (0.015 g, 0.03 mmol) and 4-cyclopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid (see WO 2011009687, 0.04 mmol) to obtain the title compound (10 mg, 46%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCl.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:12])[CH2:10][NH:20][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: ClCl
Solvent: ClCCl
Product: O=C(CNC1CCCC1)OCc1ccccc1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
A solution of Benzyl-2-bromoacetate (3.30 ml, 20.0 mmol) in 20 mL CH2 Cl2 was added drop-wise to a solution of cyclopentylamine (8.60 g, 100 mmol) in 20 mL of CH2Cl2, with stirring at 0° C. On completion of the addition of benzyl-2-bromoacetate, the reaction was stirred at room temperature 17 hours. The organic solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with saturated Na2CO3 solution. The solution was extracted with 1N HCl . The aqueous layer was made basic with Na2CO3 and extracted with chloroform. The organic layer was dried (MgSO4) and evaporated. The residue was purified by silica gel flash column chromatography, eluting sequentially with hexane and hexane/ethyl acetate (1:1, v/v) to yield 2.3 g (50.0%) of the title compound as an oil. 1 H NMR (CDCl3) δ 6 1.25-1.85 (m, 9H); 3.0-3.12 (m, 1H); 3.43 (s, 2H); 5.15 (s, 2H); 7.27-7.42 (m, 5H); 13C NMR (CDCl3) δ 23.72, 32.71, 49.53, 59.03, 66.24, 128.1, 128.32, 135.42, 172.29.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(C)(C)C>Cl.C(OCC)(=O)C>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of [2-(4-Chloro-benzoyl)-phenyl]-carbamic acid tert-butyl ester (11.6 g, 0.035 mol) dissolved in 200 mL HCl/ethyl acetate is stirred at RT. The ethyl acetate is removed in vacuo. The mixture is adjusted to pH10 by addition of aqueous NaOH. The mixture is extracted with ethyl acetate, dried over NaSO4 and concentrated. This provides the desired compound. This is used without further purification.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH-].[Na+].N.O.[CH:18]1[C:34]2[CH2:33][C@H:32]3[N:35]([CH2:37][CH2:38][C@@:24]45[C@H:31]3[CH:30]=[CH:29][C@H:27](O)[C@@H:25]4[O:26][C:22]([C:23]=25)=[C:20]([OH:21])[CH:19]=1)[CH3:36]>CO.C(O)(=O)C.CCCCO.CC(C)=O.CC(O)=O>[CH3:36][N:35]1[C@@H:32]2[CH2:33][C:34]3=[CH:18][CH:19]=[C:20]([OH:21])[C:22]4[O:26][C@H:25]5[C@@H:27]([O:1][C@@H:2]6[O:10][C@H:9]([C:11]([OH:13])=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]6[OH:4])[CH:29]=[CH:30][C@@H:31]2[C@:24]5([C:23]=43)[CH2:38][CH2:37]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)[O-]
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)C=C[C@H]3[C@H]1C5
Reaction time: 20 h
Yield: 52 %

Procedure:
To a solution of the above glucuronate in MeOH (24 ml) was added 5% aqueous NaOH (6 ml) and the mixture was left to stir for 20 hours. T.l.c (n-BuOH/acetone/AcOH/5% aq.NH3 /water 45:15:10:10:20) showed that there were two components one of which was M6G and the other morphine. The solution was transferred to a beaker and was acidified with glacial acetic acid (7 ml) which took the pH of the mixture to 5.5. Shortly after this pH was reached (5 minutes), a white solid started to precipitate. The suspension was stirred for a further 30 minutes, the solid filtered and washed with MeOH, and morphine-6-glucuronide (0.4 g, 52%) was obtained after drying at 120° C. for 4 hours, m.p. 240-243° C. More M6G could be obtained by cooling the filtrate.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[CH:17]=[C:18]([C@@H:22]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=[CH:20][CH:21]=1.[N:37]1[C:46]2[NH:45][CH2:44][CH2:43][CH2:42][C:41]=2[CH:40]=[CH:39][C:38]=1[CH2:47][CH2:48]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:15][C:16]1[CH:17]=[C:18]([C@@H:22]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:48][CH2:47][C:38]3[CH:39]=[CH:40][C:41]4[CH2:42][CH2:43][CH2:44][NH:45][C:46]=4[N:37]=3)=[CH:34][CH:35]=2)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C[C@H](Cc1ccc(O)cc1)c1cccc(F)c1
Reactant: OCCc1ccc2c(n1)NCCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](Cc1ccc(OCCc2ccc3c(n2)NCCC3)cc1)c1cccc(F)c1
Yield: 61.5 %

Procedure:
Diisopropyl azodicarboxylate (0.20 mL, 1.0 mmole) was added dropwise to a solution of ethyl (S)-3-(3-fluorophenyl)-4-(4-hydroxyphenyl)butanoate (250 mg, 0.83 mmole), 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol (178 mg, 1.0 mmole), and triphenylphosphine (262 mg, 1.0 mmole) in anhydrous THF (5 mL) at RT. After 18 hr the reaction was concentrated and the residue was flash chromatographed on silica gel (5:1 Et2O/hexanes) to afford impure title compound (236 mg, 61%): MS (ES) m/e 463 (M+H)+. This was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: CC(C)(C)OC(=O)C1=Cc2cc(Br)ccc2OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CO3)cc1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
Under argon atmosphere, a solution of tert-butyl 6-bromo-2H-1-benzopyran-3-carboxylate (5.00 g), 4-methylphenyl borate (2.62 g) and potassium carbonate (4,44 g) in toluene-ethanol-water (160-16-16 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphinepalladium (0.56 g), and the mixture was refluxed for 14 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:19) to give pale yellow crystals, which were recrystallized from ethanol to give tert-butyl 6—(4-methylphenyl)-2H-1-benzopyran-3-carboxylate (3.84 g) as pale yellow crystals.
Reaction SMILES: [CH2:1]=[O:2].[CH2:3]([SH:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CCCCCC>O>[OH:2][CH2:1][S:15][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=O
Reactant: CCCCCCCCCCCCS
Solvent: CCCCCC
Solvent: O
Product: CCCCCCCCCCCCSCO
Temperature: 100 °C
Yield: 91.8 %

Procedure:
162.2 grams of a 37% by weight aqueous solution of formaldehyde (equivalent to 2 moles), 404 grams of n-dodecyl mercaptan (equivalent to 2 moles) and 250 milliliters of hexane were placed in a one liter flask equipped with an overhead azeotropic mixture condenser and a condensed water and hexane component separator. A fixed bed of Amberlyst 15 acid-type ion exchange resin catalyst was provided, and the reaction mixture in the flask was circulated by a pump from the flask through the catalyst bed and back to the flask at a rate of about 2 milliliters per minute for a time period of 4 hours. While the reaction mixture was being circulated through the catalyst bed, it was heated to a temperature of approximately 100° C. whereby the azeotropic mixture formed by the hexane and water in the flask was vaporized, withdrawn from the flask and condensed. The water component of the condensed azeotropic mixture was separated from the hexane component and withdrawn, and the hexane was returned to the reaction flask. A 91.8% yield of dodecyl hydroxymethyl sulfide was realized after the hexane was removed by vacuum evaporation.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]3[C:17]([O:19][C:20](=O)[C:8]=23)=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:17][OH:18])[C:8]=2[CH2:20][OH:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)c2c1cc1ccccc1c2-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2ccccc2c(-c2ccccc2)c1CO

Procedure:
1-Phenyl-2,3-naphthalenedicarboxylic anhydride (VII) (25 g) was added to lithium aluminium hydride (10.4 g) in refluxing tetrahydrofuran (500 ml) over 30 min. and the reactants were refluxed for a further 1 hr. Water was added and the precipitate formed was filtered off and washed with ether (3 × 500 ml). The filtrate and the combined ether washings were dried (Mg2SO4) and evaporated to dryness. The residue was recrystallised from toluene to give 1-phenyl-2,3-bis(hydroxymethyl)naphthalene (VIII) m.p. 150°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:63][CH2:64][CH3:65])[C@@H:5]([N:7]([CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[C:57]2[C:62]=1[N:61]=[CH:60][CH:59]=[CH:58]2)[C:8](=[O:51])[C@@H:9]([NH:33]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:6])[CH3:2].N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:33][C@@H:9]([CH2:10][C:11]([NH:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:32])[C:8]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:3][CH2:1][CH3:2])[O:63][CH2:64][CH3:65])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[C:57]2[C:62]=1[N:61]=[CH:60][CH:59]=[CH:58]2)=[O:51]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
(9H-Fluoren-9-yl)methyl (S)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1,4-dioxo-4-(tritylamino)butan-2-ylcarbamate (Compound III-20) 23.4 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 15.3 g, (yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[CH:5]=[O:6].[CH:12]([Mg]Br)=[CH:13][CH2:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[CH:5]([OH:6])[CH2:15][CH2:14][CH:13]=[CH2:12]
Reactant: COc1ccc(F)cc1C=O
Reactant: CCC=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(O)c1cc(F)ccc1OC
Yield: 79.8 %

Procedure:
To a solution of 2-methoxy-5-fluorobenzaldehyde (3.0 g, 19.5 mmol) in THF (20 mL) at 0° C. was added a solution 1-butenylmagnesium bromide (0.5 M in THF, 45 mL, 22.5 mmol) dropwise for 15 min. Then the reaction mixture was poured to a solution of saturated ammonium chloride (80 mL) in a separatory funnel. The organic fraction was extracted with ethyl acetate (3×60 mL) and the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The solvent then was removed in vacuo and crude product thus obtained was purified by flash column chromatography (10% EtOAc in hexane, Rf=0.11) to give the product as an oil (3.27 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[O:32]1[C:40]2[CH:39]=[CH:38][N:37]=[C:36]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[C:35]=2[CH:34]=[CH:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:44]4[CH2:45][CH2:46][N:41]([C:36]5[C:35]6[CH:34]=[CH:33][O:32][C:40]=6[CH:39]=[CH:38][N:37]=5)[CH2:42][CH2:43]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1cc2occc2c(N2CCNCC2)n1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2nccc3occc23)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-furo[3,2-c]pyridinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=633.99 (M+H+); retention time=0.64 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[N:5]([CH2:12][CH2:13][NH:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21](Br)=[CH:22][N:23]=2)[N:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[C:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])[NH2:27].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.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].O>[CH2:1]([O:3][C:4](=[O:25])[N:5]([CH2:12][CH2:13][NH:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:32]3[CH:33]=[CH:34][C:29]([C:26](=[O:28])[NH2:27])=[CH:30][CH:31]=3)=[CH:22][N:23]=2)[N:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)N(CCNc1ccc2ncc(Br)n2n1)c1ccccc1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N(CCNc1ccc2ncc(-c3ccc(C(N)=O)cc3)n2n1)c1ccccc1
Temperature: 85 °C

Procedure:
To a mixture of [2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-phenyl-carbamic acid ethyl ester (354.7 mg, 0.9 mmol), (4-carbamoylphenyl)boronic acid [123088-59-5] (174.2 mg, 1.1 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (368.8 mg, 1.6 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (74.4 mg, 0.1 mmol) contained in a 25 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (13 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 17 h then cooled and partitioned between brine and ethyl acetate. The phase separated extract was dried (MgSO4), evaporated, flash chromatographed (silica gel eluted with 10% (v/v) methanol/ethyl acetate) and further purified by preparative RP-HPLC to provide {2-[3-(4-carbamoyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethyl}-phenyl-carbamic acid ethyl ester as a white powder, mp. 227-228° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.07 Hz, 2H) 2.51 (dt, J=3.73, 1.80 Hz, 2H) 3.31 (s, 1H) 3.48 (q, J=6.23 Hz, 2H) 3.91-4.04 (m, 3H) 6.69 (d, J=9.85 Hz, 1H) 7.18-7.35 (m, 5H) 7.76 (d, J=9.85 Hz, 1H) 7.91-8.01 (m, 3H) 8.21 (d, J=8.59 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 14.25, 48.18, 60.95, 112.37, 124.91, 125.75, 126.00, 126.35, 127.18, 127.79, 128.77, 130.81, 131.93, 132.15, 137.57, 141.78, 153.40, 154.85, 167.49. LRMS (ESI) m/z 445.1 [(M+H)]+, calc'd for C24H24N6O3: 444.50.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:10]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)=[O:12])[S:8][C:6]=2[N:7]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=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]>[CH2:29]([C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:10]=[C:9]([C:11]([N:13]4[CH2:16][CH:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:14]4)=[O:12])[S:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: O=C(c1nc2c(N3CCOCC3)nc(Cl)nc2s1)N1CC(N2CCOCC2)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CC(N4CCOCC4)C3)sc2n1
Temperature: 150 °C

Procedure:
A mixture of (5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)-(3-morpholin-4-ylazetidin-1-yl)methanone (98 mg, 0.23 mmol), 2-ethylbenzimidazole (36 mg, 0.25 mmol), tris(dibenzylideneacetone)dipalladium (6 mg, 2.5 mol %), XPhos (10 mg, 9 mol %) and Cs2CO3 (107 mg, 0.33 mmol) in DMF (3 mL) was purged with argon then heated at 150° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-4%) then triturated with EtOAc affording 846 as a white solid (61 mg, 50%). LCMS (method I): RT 2.96 min, [M+H]+ 535.3. 1H NMR (CDCl3, 400 MHz): δ 8.09-8.05 (1 H, m), 7.80-7.75 (1 H, m), 7.31-7.30 (2 H, m), 4.68-4.67 (1 H, m), 4.60-4.20 (4 H, brd s), 4.52 (1 H, dd, J=10.01, 5.05 Hz), 4.33-4.27 (1 H, m), 4.17 (1 H, dd, J=10.73, 5.02 Hz), 3.89 (4 H, t, J=4.65 Hz), 3.78 (4 H, t, J=4.57 Hz), 3.42-3.33 (3 H, m), 2.52-2.35 (4 H, m), 1.46 (3 H, t, J=7.44 Hz)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][N:19]2[C:25](=[O:26])[C@@H:24]([NH:27][C:28](=[O:40])[C@@H:29]([N:31](C)[C:32](=O)OC(C)(C)C)[CH3:30])[C@H:23]([CH3:41])[N:22]([C:42]([CH:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:43])[C:21]3[CH:50]=[CH:51][CH:52]=[CH:53][C:20]2=3)=[N:10]1)#[N:2].[ClH:54]>O1CCOCC1.CCOCC>[ClH:54].[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][N:19]2[C:25](=[O:26])[C@@H:24]([NH:27][C:28](=[O:40])[C@@H:29]([NH:31][CH3:32])[CH3:30])[C@H:23]([CH3:41])[N:22]([C:42]([CH:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)=[O:43])[C:21]3[CH:50]=[CH:51][CH:52]=[CH:53][C:20]2=3)=[N:10]1)#[N:2]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2nn(-c3ccccc3C#N)c3ccccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2nn(-c3ccccc3C#N)c3ccccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C
Yield: 81 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-1-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (128 mg, 178 μmol) in 4 M HCl in dioxane (889 μl) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (94.1 mg, 81%) as an off-white solid. MS m/z 620 (MH)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:20]2[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].C(OCC)(=O)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[O:19]1[C:20]2[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:15][NH:16][CH2:17][CH2:18]1
Reactant: CC(=O)c1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccccc1-c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A mixture of tert-butyl 9-(2-acetylphenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (190 mg, 0.517 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (132 mg, 84.1%) as a solid.