Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[N:29](C(OCC(C)C)=O)[CH:30]=[CH:31][N:32]=5)=[CH:24][CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].CO.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O>[NH:29]1[CH:30]=[CH:31][N:32]=[C:28]1[C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:20]=[CH:21][C:15]3[O:14][CH2:13][CH2:12][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:17][C:16]=3[CH:18]=2)=[CH:23][CH:24]=1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CN(C(=O)N2CCC(C#N)CC2)CCO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#CC1CCN(C(=O)N2CCOc3ccc(-c4ccc(-c5ncc[nH]5)cc4)cc3C2)CC1
Yield: 64.7 %

Procedure:
2-Methylpropyl 2-(4-{4-[(4-cyanopiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}phenyl)-1H-imidazole-1-carboxylate (296 mg, 0.56 mmol) was taken into methanol (10 mL), THF (2 mL) and water (0.5 mL) then warmed to give a homogeneous solution. Potassium carbonate (160 mg, 1.15 mmol) and the mixture was stirred for 30 minutes. The mixture was then concentrated and partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel chromatography (10% ethanol in ethyl acetate) to give 1-({7-[4-(1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl}carbonyl)piperidine-4-carbonitrile (155 mg, 65% yield). 1H NMR (400 MHz, d4-methanol): 7.92 (d, 2H), 7.69 (d, 2H), 7.56 (d, 1H), 7.51 (dd, 1H), 7.15 (s, 2H), 7.04 (d, 1H), 4.51 (s, 2H), 4.21 (tr, 2H), 3.70 (tr, 2H), 3.49-3.43 (m, 2H), 3.13 (m, 2H), 2.97 (m, 1H), 1.98-1.93 (m, 2H), 1.86-1.78 (m, 2H). MS (EI) for C25H25N5O2: 429 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[CH:6][C:5]=1[O:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[CH:6][C:5]=1[O:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)NC2(C(=O)O)CCCCCC2)cc1OCCc1cccc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)CCCCCC3)ccc2C(C)O)c1
Reaction time: 72 h
Yield: 16.6 %

Procedure:
The compound of example 60 (300 mg, 0.686 mmol) was dissolved in methanol (6 ml) and cooled in an ice bath. Sodium borohydride (79 mg, 2.06 mmol) was added, the mixture was kept at 0° C. for 72 h, and then evaporated to dryness. The residue was partitioned between EA and 2 N hydrochloric acid, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was stirred with diethyl ether and the solidified material was filtered and dried in vacuo to yield the title compound (50 mg). From the mother liquor a further batch of the title compounds was isolated by RP HPLC (water/ACN gradient).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[CH2:31]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32]1.C(N(CC)CC)C.O>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([N:36]2[CH2:37][CH2:38][C:33]3([CH2:31][CH2:32]3)[CH2:34][CH2:35]2)[N:8]=1
Reactant: C1CC2(CCN1)CC2
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CCC4(CC3)CC4)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 8 h
Yield: 27.7 %

Procedure:
In THF (15 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (134 mg, 0.30 mmol) and 6-azaspiro[2.5]octane (50 mg, 0.45 mmol). Triethylamine (61 mg, 0.60 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 8 h, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=80/1) to give a white solid (41 mg, 28% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH:14]=[O:15])[CH3:9].O.Cl>CCOCC.C([Li])CCC.C1COCC1>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:15])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH3:9]
Reactant: Brc1ccccn1
Reactant: CCOc1cc(C=O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cc(C(O)c2ccccn2)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 2-bromopyridine (4.0 g) in dry ether (50 ml), n-butyl lithium (19.2 ml, 1.6M hexane solution) was added dropwise under argon atmosphere at −78° C. After finishing the dropping, the mixture was stirred for 1 hour, and a solution of 3-ethoxy-4-nitrobenzaldehyde (5.0 g) in dry ether (100 ml) and dry THF (50 ml) was added dropwise to the mixture. After finishing the dropping, and the mixture was allowed to be at room temperature and the mixture was stirred overnight. Water was added to the mixture, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), to give (3-ethoxy-4-nitrophenyl)(2-pyridyl)methanol (3.4 g) as dark brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH:15]=[C:10]3[CH:9]=[C:8]2[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:4][CH:3]=1>CO.C1COCC1.O.O[Li].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH:15]=[C:10]3[CH:9]=[C:8]2[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:35][CH:36]=1
Reactant: CCOC(=O)CCc1cc2cc(OCc3ccc4ccccc4n3)cnc2n1Cc1ccc(Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1cc2cc(OCc3ccc4ccccc4n3)cnc2n1Cc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
Ethyl 3-[1-(4-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionate (90 mg, 0.180 mmol) was dissolved in a mixture of MeOH:THF:H2O (1:1:1, 2 mL) and LiOH.H2O (25 mg) added. The mixture was heated to 60° C. and monitored by LCMS. After complete reaction the solution was partitioned between EtOAc and water and the aqueous layer acidified with solid citric acid to pH˜4, the organic layer separated, washed with water, dried (MgSO4), filtered and evaporated to yield the title acid. LCMS (ESI) M+H 472.
Reaction SMILES: C(=O)([O-])O.[Na+].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:38])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[C:22](=[O:33])[C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[C:25](=[O:28])[C:26]=3[CH3:27])=[CH:16][C:15]=2[O:34]C(=O)C)[CH:7]=1>CO>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:38])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[C:22](=[O:33])[C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[C:25](=[O:28])[C:26]=3[CH3:27])=[CH:16][C:15]=2[OH:34])[CH:7]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3cccnc3)c(OC(C)=O)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3cccnc3)c(O)c2)=C(C)C1=O
Reaction time: 1 h
Yield: 56.2 %

Procedure:
An aqueous saturated sodium hydrogencarbonate solution (4 ml) was added to a methanol solution (10 ml) of N-(pyridin-3-yl)-4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (55 mg, 0.122 mmol) and the resulting solution was stirred for 1 hour. The reaction solution was extracted with ethyl acetate, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (benzene:acetone=3:1) to obtain the titled compound (28 mg, 0.0686 mmol, 56%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16](Cl)=[O:17].C(N(CC)CC)C.O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:16]([C:15]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([C:12]([F:11])([F:25])[F:24])[CH:14]=2)=[O:17])[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: c1cc2c(cn1)NCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)N2CCOc3ccncc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 50 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (1.0 g, 7.34 mmol) and 3-trifluoromethyl-4-methoxy-benzoyl chloride (2.1 g, 8.80 mmol) were dissolved in dichloromethane. Triethylamine (2.0 ml, 14.68 mmol) was added thereto and then stirred at room temperature for 4 hours. To the reaction mixture, water was added to quench the reaction and the mixture was extracted with dichloromethane, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:21])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][NH:12]2)=[CH:8][CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:21])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][N:12]2[C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: CC1(c2ccccc2)CNc2cc(Br)ccc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CC(C)(c2ccccc2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.2 %

Procedure:
Acetyl chloride (163 μL, 2.29 mmol) and TEA (313 μL, 2.29 mmol) were added to a solution of 6-bromo-3-methyl-3-phenyl-2,3-dihydro-1H-indole (600 mg, 2.1 mmol) in DCM (20 mL) at 0° C. The reaction was stirred for 45 minutes at room temperature and then quenched with 1 M aqueous HCl and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound (660 mg) as a yellow solid. MS: [M+H]+=330.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:3].[H][H].CCOCC>Cl>[NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]1)([CH3:9])[CH3:8])[CH3:3]
Reactant: CC(N)CCCC(C)(C)c1ccc(N)cc1
Reactant: [H][H]
Agent: Cl
Solvent: CCOCC
Product: CC(N)CCCC(C)(C)[C@H]1CC[C@H](N)CC1
Temperature: 25 °C

Procedure:
5.0 Parts of 2-amino-6-(4-aminophenyl)-6-methylheptane dissolved in 68 parts of 1N aqueous hydrochloric acid were shaken at room temperature and atmospheric pressure with hydrogen in the presence of 0.5 parts of Nishimura catalyst (rhodium-platinum oxides). Hydrogen uptake ceased at 105% of theory and the solution was filtered free of catalyst and treated with sodium hydroxide solution to give an oil which was isolated with ether. After removing the ether the residue was distilled to give 4.0 parts of cis and trans-2-amino-6-(4-aminocyclohexyl)-6-methyl-heptane b0.3 120°-9° with the following percentage composition by weight.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=[CH:41]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=[CH:41]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCCn3cnc4ccccc43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)ccc(OCCCCn3cnc4ccccc43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[4-(benzimidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14]C)[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)CCC>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].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[C:9]([OH:14])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c(-c2ccco2)c1O
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
A solution of tri(2-furyl)phosphine (0.026 g) and tris(dibenzylideneacetone)dipalladium (O) (0.026 g) in toluene (50 mL) was allowed to stir for 10 minutes. To this solution was added 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz-[b]azepine (1.0 g), followed by 2-tributylstannylfuran (1.2 g). The reaction was heated to reflux for 0.5 hour, was allowed to cool, and the toluene was evaporated. The residue was triturated with hot hexanes (75 mL). The isolated solid was recrystallized from ethyl acetate/hexanes (1:1) to afford the title compound (0.44 g); mp 233°-234° C.; NMR: 11.47 (bs, 1), 7.79 (s, 1), 7.58 (d, 1, J=8.9), 7.34-7.31 (m, 2), 6.91 (d, 1, J=3.4), 6.61 (m, 1), 3.82 (s, 3). Analysis for C15H10ClNO4 0.5 H2O.: Calculated: C, 57.61; H, 3.54; N, 4.47; Found C, 57.77; H, 3.13; N, 4.46.
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:17][C:18]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:20][CH2:19]2)=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([C:18]3([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:20][CH2:19]3)[C:15](=[O:16])[CH:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1
Reactant: O=C(NC1(c2ccc(Cl)cc2)CC1)C1COCCN1c1nc(Cl)ncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1C1(c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x35 using 4-(5-bromo-2-chloropyrimidin-4-yl)-N-(1-(4-chlorophenyl)cyclopropyl)morpholine-3-carboxamide (PREPARATION x33, 300 mg, 0.635 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (27.6 mg, 0.048 mmol), palladium (II)acetate (7.13 mg, 0.032 mmol), and potassium phosphate, tribasic (189 mg, 0.890 mmol) in dioxane (2.5 mL) and tert-butanol (0.5 mL). ESI-MS m/z [M+H]+ calc'd for C19H17Cl2N3O2, 391.07. found 391.0.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[CH2:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][CH2:21][N:16]2[C:17]([CH3:20])=[CH:18][CH:19]=[C:15]2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[CH:26][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(O)cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of 2-(4-benzyloxyphenyl)-1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrole (1.15 g, 2.26 mmol) in ethanol (60 ml) and tetrahydrofuran (30 ml) was added 10% palladium carbon (200 mg) and the mixture was stirred for 4 hours under hydrogen atmosphere. The insoluble matter was filtered out and the filtrate was concentrated to give the object compound as an oily substance. 920 mg (yield: 98.0%)
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([NH:25][C:26]3[N:31]=[C:30]([CH:32]4[CH2:34][CH2:33]4)[C:29]([F:35])=[CH:28][N:27]=3)[CH:19]=2)=[CH:16][N:17]=1)([OH:12])[CH3:11])(C(C)(C)C)(C)C.Cl>CO>[CH:32]1([C:30]2[C:29]([F:35])=[CH:28][N:27]=[C:26]([NH:25][C:20]3[CH:19]=[C:18]([C:15]4[S:14][C:13]([C:10]([OH:12])([CH3:11])[CH2:9][OH:8])=[N:17][CH:16]=4)[CH:23]=[C:22]([F:24])[CH:21]=3)[N:31]=2)[CH2:33][CH2:34]1
Reactant: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ncc(-c2cc(F)cc(Nc3ncc(F)c(C4CC4)n3)c2)s1
Agent: Cl
Solvent: CO
Product: CC(O)(CO)c1ncc(-c2cc(F)cc(Nc3ncc(F)c(C4CC4)n3)c2)s1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of the product of Step 5 (150 mg, 0.289 mmol) in methanol (4 mL) was added HCl (4.0 M in dioxane) (0.072 mL, 0.289 mmol). After 30 minutes, the reaction mixture was concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 2-(5-{3-[(4-cyclopropyl-5-fluoropyrimidin-2-yl)-amino]-5-fluorophenyl}-1,3-thiazol-2-yl)propane-1,2-diol (95 mg, 0.24 mmol, 81%). MS ESI: [M+H]+ m/z 405.1. 1H NMR (600 MHz, DMSO-d6) δ9.83 (s, 1H); 8.41 (s, 1H); 8.01 (s, 1H); 7.75 (s, 1H); 7.53 (d, J=11.4 Hz, 1H); 7.06 (d, J=9.6 Hz, 1H); 5.89 (s, 1H); 4.89 (s, 1H); 3.52 (s, 2H); 2.29-2.22 (m, 1H); 1.43 (s, 3H); 1.20-1.12 (m, 4H). rhSYK activity=+++
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].CO[C:11]([C:13]1[N:14]=[N:15][N:16]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.O>C1(C)C=CC=CC=1>[F:36][C:35]([F:37])([F:38])[C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=1)[CH2:24][N:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:13]([C:11]2[NH:7][CH2:6][CH2:5][N:8]=2)[N:14]=[N:15]1
Reactant: NCCN
Reactant: COC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cc(Cn2nnc(C3=NCCN3)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 19 %

Procedure:
To a solution of Me3Al (1.36 mL, 2M soln in toluene) at 0° C. under N2, add ethylenediamine (185 μL, 0.36 mmol) and stir for several minutes warming to RT. Add 1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (750 mg, 1.69 mmol) dissolved in toluene to this solution. Reflux reaction for 3.5 hours at 110° C. Cool to RT and stir for 12 hours. Quench reaction with MeOH (2 mL), add H2O (2 mL) and extract with CH2Cl2 (4 mL×2). Dry over Na2SO4 and concentrate to afford title compound (30 mg, 4%). MS (IS) 440.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:21]Br.N>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[C:5]([Br:21])=[CH:4][N:3]=1
Reactant: Nc1nccc(NCC2(CO)CCC2)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc(Br)c(NCC2(CO)CCC2)n1
Temperature: 110 °C
Yield: 72.4 %

Procedure:
To 2-amino-4-[[(1-hydroxymethyl-1-cyclobutyl)methyl]amino]pyrimidine (0.21 g, 1.0 mmol) was added acetic acid (3 ml) and the mixture was heated to 110° C. Sodium acetate 3 hydrate (0.18 g) was added and bromine (60 μl) dissolved in acetic acid (0.5 ml) was dropwise added at 70° C. After cooling, water was added to the reaction mixture and the mixture was neutralized with aqueous ammonia under ice-cooling, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was recrystallized from acetone to give colorless prism crystals (0.21 g, 72.4%), m.p. 156-158° C. (acetone).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:25])=O>CN(C=O)C>[Cl:25][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCOCC1
Yield: 68 %

Procedure:
A mixture of 6-methoxy-7-(2-morpholinoethoxy)-3,4-dihydroquinazolin-4-one (310 mg, 1.02 mmol), thionyl chloride (10 ml) and DMF (2 drops) was heated at reflux for 4 hours and allowed to cool. Excess thionyl chloride was removed by evaporation and the residue was azeotroped with toluene. The residue was partitioned between aqueous sodium hydrogen carbonate and methylene chloride. The organic layer was separated, washed with brine and filtered through phase separating paper. The volatiles were removed by evaporation and the residue purified by column chromatography eluting with methylene chloridelinethanol (96/4) to give 4-chloro-6-methoxy-7-(2-morpholinoethoxy)quinazoline (225 mg, 68%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=2)[CH:7]=1.[OH-].[Li+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(I)cn2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)nc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (1.5 g) in a mixture of THF (10 ml) and water (10 ml) was added aqueous lithium hydroxide (381 mg), and the resulting mixture was stirred for 16 h at room temperature. The mixture was concentrated in vacuo, and partitioned between EtOAc and water. The organic layer was neutralized with 2 M HCl. The mixture was extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo to give the title compound (1 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([O:22][NH2:23])[CH:20]=[CH2:21]>>[CH2:19]([O:22][NH:23][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1])[CH:20]=[CH2:21]
Reactant: C=CCON
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Product: C=CCONC(=O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
N-allyloxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.20 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.36 mmol of O-allyl-hydroxylamine. LC/MS [9.30 min; 430 (M+1)]