Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]12[CH2:25][CH:24]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:26])[C:16](=[O:27])[CH:15]1[CH:11]([CH2:12][CH:13]([O:28][C:29]3[C:38]4[C:33](=[C:34]([CH3:41])[C:35]([O:39][CH3:40])=[CH:36][CH:37]=4)[N:32]=[C:31]([C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[N:43]=4)[CH:30]=3)[CH2:14]1)[C:10](=[O:49])[NH:9]2)=[O:7])C.CO.C(O)(=O)C>C1COCC1.O>[CH3:48][C:44]1[N:43]=[C:42]([C:31]2[CH:30]=[C:29]([O:28][CH:13]3[CH2:12][CH:11]4[CH:15]([C:16](=[O:27])[N:17]([CH3:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]5[C:8]([C:6]([OH:7])=[O:5])([NH:9][C:10]4=[O:49])[CH2:25]5)[CH2:14]3)[C:38]3[C:33](=[C:34]([CH3:41])[C:35]([O:39][CH3:40])=[CH:36][CH:37]=3)[N:32]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4cccc(C)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3cccc(C)n3)nc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
LiOH (0.42 mL, 1M) was added to a solution of 17-[2-(6-methylpyridin-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo-[13.3.0.04,6]octadec-7-ene-4-carboxylic acid ethyl ester (101, 27 mg, 0.042 mmol) in a mixture of THF:MeOH:H2O, 2:1:1 (6 mL). The resulting solution was stirred at room temperature overnight, then the pH was adjusted to 6 with acetic acid. The reaction mixture was successively diluted with water, extracted with CH2Cl2, dried (MgSO4), filtered and evaporated to give 17 mg (65%) of the title compound: m/z=613 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH3:23].C(O)(=O)/C=C/C(O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OC1(c2cc(Cl)cc(Cl)c2)CCNC1
Reactant: CCI
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(O)(c2cc(Cl)cc(Cl)c2)C1

Procedure:
Preparation according to Example 8: 3-(3,5-dichlorophenyl)pyrrolidin-3-ol (0.34 g, 1.46 mmol), acetonitrile (24 mL), sodium carbonate (0.20 g, 3.65 mmol), iodoethane (0.23 g, 1.46 mmol). Heated at reflux for 15 minutes. Yield: 0.24 g. The amine was converted to the fumaric acid salt and evaporated to a solid residue. MS m/z (relative intensity, 70 eV) 259 (M+, 5), 244 (5), 173 (4), 145 (44), 71 (bp).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:36][NH2:37]>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:37][N:36]=1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)OC[C@H]2C)n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-2-morpholinecarboxamide (302 mg, 0.66 mmol) and hydrazine monohydrate (0.41 mL, 13.18 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. in a sealed tube for 18 hours. The reaction mixture was cooled and concentrated in vacuo, and the residue was purified by flash chromatography (60 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (239 mg) as a light yellow solid. LC-MS (ES) m/z=473 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (d, J=6.6 Hz, 3H), 2.77-3.02 (m, 4H), 3.78 (d, J=11.2 Hz, 1H), 3.88 (d, J=11.1 Hz, 1H), 4.02 (dd, J=11.2, 2.9 Hz, 1H), 4.27-4.41 (m, 2H), 4.41-4.85 (bs, 2H), 5.39 (s, 2H), 6.51-6.72 (m, 2H), 7.19-7.38 (m, 5H), 7.62 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.99 (s, 1H), 8.54 (t, J=6.2 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO.O>CC(C)=O>[O:1]=[C:2]([CH3:14])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1
Reactant: CCOC(=O)c1cc(CC(C)O)on1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cc(CC(C)=O)on1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Ethyl 5-(2-hydroxypropyl)isoxazole-3-carboxylate (1.5 g, 7.53 mmol) was dissolved in acetone (40 ml) and cooled to 0° C. Jones' reagent (5.90 ml, 7.91 mmol) was added dropwise and the reaction mixture was stirred at 0 C for 30 min. Then the reaction mixture was allowed to warm up to RT and stirred 18 h. Mixture of methanol (30 ml) and water (30 ml) was added and then the volatiles were evaporated. The residue was extracted with DCM, dried with Na2SO4 and evaporated to dryness to afford 1.38 g (93%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): 6, 1.32 (t, 3H), 2.22 (s, 3H), 4.29-4.44 (m, 2H), 4.22 (s, 2H), 6.67 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])[CH3:3].[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:7][C:6]1[CH:5]=[C:4]([C@@H:2]([NH:1][C:14]2[CH:15]=[N:16][CH:17]=[C:12]([Cl:11])[N:13]=2)[CH3:3])[CH:10]=[CH:9][CH:8]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C[C@H](N)c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A mixture of 3-[(1S)-1-aminoethyl]aniline (7.5 g, 55 mmol), 2,6-dichloropyrazine (12.3 g, 82.5 mmol) and potassium carbonate (15.2 g, 110 mmol) in dioxane (140 mL) was heated at reflux for 3 days. After this time the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give an orange oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (11.6 g, 85%) as a beige solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]([CH3:9])[N:5]([C:10]2[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH2:17])[N:11]=2)[CH2:4]1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])#[N:19]>O1CCOCC1.C([O-])(O)=O.[Na+].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>[NH2:17][C:12]1[N:13]=[C:14]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([F:29])[CH:22]=2)[CH:15]=[C:10]([N:5]2[C@H:6]([CH3:9])[CH2:7][O:8][C@H:3]([CH2:2][NH2:1])[CH2:4]2)[N:11]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(Cl)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Yield: 59.7 %

Procedure:
A mixture of 4-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-6-chloro-2-pyrimidinamine (0.809 g, 3.14 mmol) and (4-cyano-3-fluorophenyl)boronic acid (1.038 g, 6.29 mmol) in 1,4-dioxane (30 mL) and saturated aqueous NaHCO3 (10 mL) was degassed with nitrogen for 10 minutes. Pd(PPh3)4 (0.185 g, 0.16 mmol) was then added and the mixture was stirred at reflux under nitrogen for 16 hours. The mixture was then cooled and slowly quenched with 1 M HCl (75 mL), then washed with EtOAc (2×75 mL). The aqueous phase was then neutralized with saturated aqueous NaHCO3, brought to about pH 10 with saturated aqueous Na2CO3, and then extracted with 90/10 CH2Cl2/IPA (3×100 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient). The product fractions were concentrated and azeotroped a few times with CH3CN to give the title compound (642 mg) as a yellow solid. LC-MS (ES) m/z=343 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([Cl:11])[CH:3]=1.ClC1C=C(Cl)C=CC=1C1[C:25]([C:26]2[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[CH:24][N:23]=[C:22]([NH:32][CH2:33][CH2:34][NH:35][C:36]2[N:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)[N:21]=1>>[Cl:11][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:5]=1[C:6]1[C:25]([C:26]2[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[CH:24][N:23]=[C:22]([NH:32][CH2:33][CH2:34][NH:35][C:36]2[N:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)[N:21]=1
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(F)cc2Cl)n1

Procedure:
6-[(2-{[4-(2-chloro-4-fluorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]-amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 4-fluoro-2-chlorobenzoyl chloride using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: C[O:2][C:3]([C:5]1([Cl:30])[C:7]2([CH2:12][CH2:11][C:10]([C:28]#[N:29])([C:13]3[C:21]4[C:20]5[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=5[O:18][C:17]=4[C:16]([O:26][CH3:27])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[O:6]1)=[O:4].C[O-].[Na+].Cl>C(O)C.O>[Cl:30][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:8][CH2:9][C:10]([C:28]#[N:29])([C:13]3[C:21]4[C:20]5[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=5[O:18][C:17]=4[C:16]([O:26][CH3:27])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)[O:6]1
Reactant: COC(=O)C1(Cl)OC12CCC(C#N)(c1ccc(OC)c3oc4ccccc4c13)CC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2(C#N)CCC3(CC2)OC3(Cl)C(=O)O)c2c1oc1ccccc12

Procedure:
At room temperature and under nitrogen, to a solution of 2-chloro-6-cyano-6-(4-methoxy-dibenzofuran-1-yl)-1-oxa-spiro[2.5]octane-2-carboxylic acid methyl ester (0.300 g, 0.0007 mol) (as obtained in step 1) in a mixture of ethanol (5 ml) and water (0.15 ml) was added sodium methoxide (0.190 g, 0.0035 mol). The reaction mass was refluxed for 1 hr, and once the product has formed, the reaction mass was brought to room temperature and the pH was adjusted to 2 with dil. HCl and extracted with Ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under vacuum to get the 2-chloro-6-cyano-6-(4-methoxy-dibenzofuran-1-yl)-1-oxa-spiro[2.5]octane-2-carboxylic acid. Yield 0.180 g (64%)
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([N-]C(C)C)([CH3:25])[CH3:24].[Li+].C(Br)C=C>C1COCC1>[CH2:25]([C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])[CH:23]=[CH2:24]
Reactant: COC(=O)C(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(C(=O)OC)(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of dimethyl 2-(4-phenoxyphenyl)malonate (2.56 g, 8.54 mmol) in dry THF (50 mL) was cooled to −78° C. and then lithium diisopropylamide (4.7 mL of a 2M solution in ThF, 9.8 mmol) was added. The reaction was stirred at −78° C. for 1 hour and then allyl bromide (11.4 mg, 9.4 mmol) was added. The reaction was stirred at −78° C. for 3 hours and then allowed to warm to room temperature and heated in a 75° C. oil bath until the reaction was shown to be complete by TLC. The reaction was cooled to room temperature and quenched with 1N HCl. Extraction with ether and drying of the ether extracts (MgSO4) gave crude product. Purification by filtration through silica gel 60 (70-230 mesh) using EtOAc, followed by HPLC (porasil) using 11% EtOAc/hexanes gave 1.8 g of dimethyl 2-(2-propenyl)-2-(4-phenoxyphenyl)malonate as a viscous oil: 1H NMR (200 mHz, CDCl3) δ 7.4-6.85 (9H, m), 5.75 (1H, m), 5.05 (2H, m), 3.75 (6H, s), 3.1 (2H, d).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=2[O:16][CH2:17][CH3:18])[CH2:4][CH2:3]1.[Br-].[CH2:20]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH:30](=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=2[O:16][CH2:17][CH3:18])[CH2:4][CH2:3]1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CCOc1c(NC2CCC(=O)CC2)ccnc1C
Reactant: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCCCCCCC=C1CCC(Nc2ccnc(C)c2OCC)CC1
Yield: 51 %

Procedure:
Preparation was carried out analogously to Example 27 from 4-(4-oxocyclohexylamino)-3-ethoxy-2-methylpyridine and undecyl triphenylphosphonium bromide. Yield: 51%
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10]3[C:15]([C:16]#[C:17][Si](C)(C)C)=[CH:14][N:13]=[C:12]([C:22]4[S:26][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:24][CH:23]=4)[N:11]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+]>CO>[CH:1]1([C:4]2[NH:5][N:6]=[C:7]([NH:9][C:10]3[C:15]([C:16]#[CH:17])=[CH:14][N:13]=[C:12]([C:22]4[S:26][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[CH:24][CH:23]=4)[N:11]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)c1ccc(-c2ncc(C#C[Si](C)(C)C)c(Nc3cc(C4CC4)n[nH]3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(-c2ccc(C(C)(C)O)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
A mixture of 2-(5-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)thiophen-2-yl)propan-2-ol (115 mg, 0.26 mmol), K2CO3 (72 mg, 0.52 mmol, 2.0 equiv.) in CH3OH (10 ml) was stirred at room temperature for 1 h. The mixture was filtered. The solid was washed with water and extracted with EtOAc. The extract was washed by brine, dried (Na2SO4), filtered and concentrated. The residue was recrystalized by ether to give compound 2-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophen-2-yl)propan-2-ol (Compound 180) (53 mg, 55%). LC-MS (m/z)=366.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.73-0.77 (m, 2H), 0.96-1.01 (m, 2H), 1.54 (s, 6H), 1.91-1.97 (m, 1H), 4.83 (s, 1H), 5.60 (s, 1H), 6.52 (s, 1H), 7.01 (d, J=4.0 Hz, 1H), 7.69 (d, J=4.0 Hz, 1H), 8.63 (s, 1H), 8.45 (s, 1H), 8.56 (bs, 1H), 12.24 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[CH:13]1([CH2:19][O-:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Na+]>C1(CO)CCCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:20][CH2:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: [O-]CC1CCCCC1
Agent: OCC1CCCCC1
Agent: [Na+]
Solvent: O
Product: Brc1ccc2nccc(OCC3CCCCC3)c2c1
Temperature: 120 °C
Yield: 71.3 %

Procedure:
To a solution of 6-bromo-4-chloro-quinoline (0.550 g, 2.27 mmol) in cyclohexylmethanol (5 mL) was added a solution of sodium cyclohexylmethoxide (11.34 mmol, prepared from cyclohexylmethanol and sodium) at room temperature. Then, the reaction mixture was heated to 120° C. for 15 h in a sealed reaction flask. After cooling to room temperature, the reaction mixture was diluted with water and the solvent was removed under the vacuum. Then, the remaining aqueous solution was neutralized with 3.0N hydrochloric acid and the organic compound was extracted into ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 0.518 g (71% yield) of 6-bromo-4-cyclohexylmethoxy-quinoline as a light yellow oil: EI-HRMS m/e calcd for C16H18BrNO (M+) 320.2304, found 320.2314.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[F:10][C:11]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:12]=1[CH2:13]Br>C(O)C>[F:10][C:11]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:12]=1[CH2:13][S:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: Sc1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1c(F)c(F)c(CSc2ncccn2)c(F)c1F
Reaction time: 0.75 h

Procedure:
To a mixture of 0.47 g of 2-mercapto-pyrimidine in 15 ml 95% ethanol was added 0.18 g of NaOH. The mixture was stirred 45 min. until an amber solution resulted; then 1 g of 2,3,4,5,6-pentafluorobenzyl bromide was added. The adduct precipitated within five minutes. Stirring continued for one hour. Filtration of the mixture yielded 0.26 g, mp 89°-92° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][NH:8][CH2:9][C:2]=12.[H-].[Na+].I[CH2:13][CH3:14]>C1COCC1>[CH2:13]([N:8]1[CH2:7][C:3]2[C:2](=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9]1)[CH3:14]
Reactant: CCI
Reactant: c1cnc2c(c1)CNC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1Cc2cccnc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (5.00 g) in THF was added 80% NaH (3.00 g) at rt. The reaction mixture was stirred for 30 min at room temperature, and 5.3 mL of iodoethane was added dropwise. The reaction mixture was stirred for another 5 h, then quenched with ice water, and extracted with CH2Cl2 (70 mL×5). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (2.80 g, 45.00%), HPLC: 90.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 149.3 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.02 (t, J=4.8 Hz, 3H), 2.64 (m, 2H), 3.62 (s, 2H), 3.95 (s, 2H), 7.11-7.83 (m, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)[CH2:8][CH2:9][CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH2:24]>>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)[CH2:8][CH2:9][CH2:10][NH:24][CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCBr)Cc1ccc2c(c1)OCO2
Reactant: CN
Product: CNCCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Benzo[1,3]dioxol-5-ylmethyl-(3-bromo-propyl)-carbamic acid tert-butyl ester (23.0 g, 61.8 mmol) was diluted in methylamine (2.00M in THF, 300 mL, 600 mmol) at rt under an atmosphere of nitrogen and stirred at ambient temperature for 16 h. The solvent was evaporated and saturated sodium carbonate solution was added. The solution was extracted with ethyl acetate (2×150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 18.2 g (91%) of benzo[1,3]dioxol-5-ylmethyl-(3-methylamino-propyl)-carbamic acid tert-butyl ester as a clear oil. [M+H]+ 323.09.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31]C(=O)C(F)(F)F)=[N:4][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[OH-].[K+]>CO.O>[NH2:31][C@@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)[N:4]=1
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NC(=O)C(F)(F)F)n3)cc2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N)n3)cc2CC1
Temperature: 60 °C

Procedure:
N-((1R,2R)-2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-2,2,2-trifluoro-acetamide (313 mg, 0.578 mmol) was dissolved in Methanol (10 mL) and 1.0 M of Potassium hydroxide in water (3.0 mL) was added. The reaction was heated at 60° C. for 7 h, at which time the reaction had reached completion by HPLC. The reaction was cooled then was poured into 30 mL satd. sodium bicarbonate-20 mL water, then extracted 4×50 mL DCM, dried over sodium sulfate and concentrated in vacuo to afford the amine as a off-white film (260 mg, 100%). LCMS (m/e) 445 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.89 (s, 1H), 7.28 (m, 2H), 7.01 (d, 1H, J=7.9 Hz), 6.79 (s, 1H), 5.14 (d, 1H, J=8.0 Hz), 3.75 (m, 1H), 3.53 (m, 2H), 3.37 (s, 3H), 2.91 (m, 4H), 2.75 (m, 6H), 2.58 (m, 1H), 2.16 (m, 1H), 2.04 (m, 1H), 1.78 (m, 2H), 1.32 (m, 6H).
Reaction SMILES: CC([O:5][C:6](=[O:24])[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][C:9]1=[O:23])(C)C.CC#N.O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:21]([O:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH2:10][C:9](=[O:23])[N:8]([CH2:7][C:6]([OH:24])=[O:5])[C:13]=2[CH:14]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)OC(C)(C)C)C(=O)CO2
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)O)C(=O)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Ethyl 4-{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (6.14 g, 18.0 mmol) was dissolved in 60 mL of a 1:1 solution of methylene chloride and trifluoroacetic acid. The mixture was allowed to stir at room temperature for three hours before it was determined to be complete by HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid). The chromatogram indicated that all of the starting material (Rt=7.7 min) was consumed and converted to the desired product (Rt=5.3 min). The volatiles were removed by rotary evaporation and the resulting residue was taken up in a minimal amount of methylene chloride and treated with a 2 M solution of hydrochloric acid in ethyl ether. After allowing the mixture to stir for several minutes, the mixture was concentrated once again by rotary evaporation to yield {6-[(ethyloxy)carbonyl]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}acetic acid (5.28 g, 17.9 mmol, 99%) as a brown amorphous solid. MS (ES) m/e 280 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]2[O:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][C:26]=1[CH3:38]>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]([OH:18])[CH2:17][NH:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:27][C:26]=2[CH3:38])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOCc1ccc(OCC2CO2)cc1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCN
Product: CCCCOCCOCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-n-butyloxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.