Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=2)[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:3]=1.[H-].[Na+].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=2)[CH:5]=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:24][CH:25]=2)[N:3]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCc1ccc2cc(-c3ccc(O)cc3)nc(F)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2cc3ccc(CCCCCCCC)cc3c(F)n2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1-fluoro-3-(4-hydroxyphenyl)-7-octylisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1-fluoro-3-[4-(octyloxy)phenyl]-7-octylisoquinoline.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:45][N:46](C(C)C)[CH:47](C)C.CNC>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:46]([CH3:47])[CH3:45])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CN(C)C)c3)c3ccccc23)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 37.1 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (17 μl, 0.1 mmol) was added dimethylamine (2.0M solution in THF) (41 μl, 0.08 mmol). The reaction mixture was heated to 40° C. and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (12 g silica, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and iso-hexane (2:1:2, 5.0 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(dimethylamino)acetamide (Example 12) as an orange solid (18 mg, 35%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 2.31 (6 H, s), 2.39 (3 H, s), 3.14 (2 H, s), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.29 (1H, d), 7.35 (2H, d), 7.44 (2H, d), 7.65-7.55 (3H, m), 7.94 (1H, m), 8.38-8.28 (3H, m), 8.59 (1H, s), 8.79 (1H, s), 9.93 (1H, s).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][CH:5]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6]1.[OH-].[Na+]>>[CH3:11][C:8]1([CH3:12])[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:13])=[O:2])[CH2:10][CH2:9]1
Reactant: COC(=O)CC1CCC(C)(C)CC1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(CC(=O)O)CC1
Yield: 95 %

Procedure:
Hydrolysis of (4,4-dimethyl-cyclohexyl)-acetic acid methyl ester (80 mg, 0.43 mmol) with NaOH following a method analogous to General Procedure G1 gave (4,4-dimethyl-cyclohexyl)-acetic acid after purification (70 mg, 95% yield). This acid (70 mg) was converted to 1-(4,4-dimethyl-cyclohexyl)-propan-2-one (60.0 mg, 89% yield) using MeLi in ethyl ether following a method analogous to General Procedure A1. Pyrrolidone hydrotribromide (190 mg, 0.38 mmol) treatment of the above ketone following a method analogous to General Procedure B1 gave 1-bromo-3-(4,4-dimethyl-cyclohexyl)-propan-2-one (70 mg).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:40][CH3:41])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[O:40][CH3:41]
Reactant: COc1ccc(N)cc1O
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(=O)c5ccc(C(C)=O)s5)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 34, 40 mg, 0.093 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (16 mg, 0.115 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 74% yield (0.038 g, 0.0686 mmol).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[O:5][C:4]([C:22]([O:24]CC)=[O:23])=[CH:3]1.[OH-].[Na+].O>C(O)C>[O:1]=[C:2]1[C:7]2[N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[O:5][C:4]([C:22]([OH:24])=[O:23])=[CH:3]1
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1ccccc1n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(=O)c2c(o1)c1ccccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.0 g (0.017 mole) of ethyl 4,5-dihydro-4-oxo-5-(phenylmethyl)pyrano [3,2-b]indole-2-carboxylate, 80 ml 1% aqueous sodium hydroxide, and 450 ml water was stirred at room temperature for 3 hr. Ethanol (~150 ml) was then added until virtually all of the insoluble material present had dissolved. After washing twice with 250 ml of chloroform, the aqueous layer was filtered by gravity, cooled in ice, and acidified with 4 N hydrochloric acid. The tan precipitate was filtered, digested for 15 min on the steam bath with 100 ml of water and re-filtered while still warm. Recrystallization of the final product from DMF-water yielded a white powder of mpt. 290°-dec.
Reaction SMILES: [Br:1]Br.[CH:3]1([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[NH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH:3]1([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:1])=[CH:15][C:14]=2[CH3:19])=[NH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Cc1ccccc1NC(=N)NC1CCCCC1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Br)ccc1NC(=N)NC1CCCCC1
Temperature: 70 °C
Yield: 153.1 %

Procedure:
A solution of bromine (0.336 g, 2.1 mmol) in glacial acetic acid (1 ml) was added dropwise to a stirred solution of N-cyclohexyl-N'-(2-methylphenyl)guanidine (0.231 g, 1 mmol) in glacial acetic acid (2 ml) at room temperature. After the addition, the addition funnel was replaced by a reflux condenser and the red reaction solution was heated on a warm water bath at 70° C. for about an hour. The reaction mixture was allowed to cool to room temperature and then poured in cold ice water (30 ml) containing a 200 mg of sodium bisulfite. The mixture was then extracted with dichloromethane (3×15 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give a colorless liquid (0.475 g). This liquid was purified on a flash silica gel column to give a bright foamy product (0.25 g), mp 89°-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH2:32])=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:33])[CH:8]=[CH:9][O:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[OH:33][CH:7]1[C:6]2[C:11](=[C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH2:32])=[O:31])[CH:28]=5)[CH:23]=[CH:22]4)[CH2:17][CH2:16]3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10][CH2:9][CH2:8]1
Reactant: COc1ccc2c(=O)ccoc2c1CCN1CCC(n2ccc3ccc(C(N)=O)cc32)CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)OCCC2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
52 mg of 1-(1-(2-(7-methoxy-4-oxo-4H-chromen-8-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide was dissolved in 6 ml of methanol-tetrahydrofuran (1:1). Thereafter, 5 mg of sodium borohydride was added to the reaction solution while cooling on ice. The obtained mixture was then stirred at room temperature for 2 hours. Thereafter, 5 mg of sodium borohydride was added to the reaction solution, and further, 5 mg each of sodium borohydride was added thereto 2 hours and 4 hours later. Thereafter, the reaction solution was stirred at the same temperature overnight. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol), so as to obtain 30 mg of the subject compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(CCC2CCCO2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(CCC3CCCO3)cc2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2-ylamine described in Manufacturing Example 1-2-3 (43.7 mg, 0.37 mmol) was added (4-(2-tetrahydrofuran-2-yl-ethyl)phenyl)-acetohydroximoyl chloride (300 mg, 1.12 mmol) described in Manufacturing Example 82-1-6 under nitrogen atmosphere at room temperature. Triethylamine (0.31 mL, 2.24 mmol) was then added dropwise and stirred for 2 hours at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:9 then 3:7) to obtain the title compound (68 mg, 53%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1

Procedure:
Similar procedure as described in example 10c was used, starting with (1R,2S)-2-phenyl-cyclopropylamine, rhodanine, mercuric chloride and DIEA to give 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one. LC-MS m/e 232 (MH+).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:27]=[N:26][C:8]2[O:9][CH2:10][CH2:11][N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:7]=2[CH:6]=1)=[NH:4].C(O)(=O)C.[CH3:32][C:33]([CH3:35])=O>>[CH3:32][C:33]1([CH3:35])[O:1][NH:2][C:3]([C:5]2[CH:27]=[N:26][C:8]3[O:9][CH2:10][CH2:11][N:12]([S:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)(=[O:15])=[O:14])[C:7]=3[CH:6]=2)=[N:4]1
Reactant: N=C(NO)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Reactant: CC(C)=O
Solvent: CC(=O)O
Product: CC1(C)N=C(c2cnc3c(c2)N(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCO3)NO1
Temperature: 80 °C
Reaction time: 48 h
Yield: 44.7 %

Procedure:
To a solution of N-hydroxy-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboximidamide (25 mg, 0.062 mmol) in acetone (2 mL) was added acetic acid (500 μL, 8.73 mmol). The reaction was heated to 80° C. and stirred at that temperature for 48 h. The reaction mixture was concentrated under reduced pressure. The resulting paste was purified by flash column chromatography using a gradient elution of hexanes with 20-100% EtOAc to provide 7-(5,5-dimethyl-2,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (12.3 mg, 0.028 mmol, 44.7% yield) as a white solid. LCMS (+ESI) m/z=443.1 [M+H]+; 1H-NMR (CDCl3) δ 8.45 (d, 1H), 8.38 (br s, 1H), 7.84 (d, 2H), 7.78 (d, 2H), 4.55 (br s, 1H), 4.02 (dd, 2H), 3.91 (dd, 2H), 1.63 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:7]2[OH:12].Cl>[Zn].C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:7]2[OH:12]
Reactant: CCCCCCCCCCCC(=O)c1ccc2c(Cl)cccc2c1O
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc2c(Cl)cccc2c1O

Procedure:
A solution of 17.4 parts of 1-(5-chloro-1-hydroxynaphthalen-2-yl)-1-dodecanone and 107 parts of 37% hydrochloric acid in 2.5 parts of ethanol was contacted with stirring at reflux during 26 hours, with 40 parts of zinc dust which has been amalgamated by treatment with 3 parts of mercuric chloride and 53 parts of 2.1% hydrochloric acid followed by washing with ethanol. The zinc amalgam was added in small portions throughout the reaction period. Upon cooling, a solid separated. After dissolution of this solid in ethanol, zinc amalgam was filtered, and cooling gave 0.5 parts of starting material which was filtered. Concentration of the filtrate, purification by recrystallization from ethanol, and column chromatography on silica gel using 1-chlorobutane as eluent gave 12 parts of 5-chloro-2-dodecyl-1-naphthalenol, m.p. 68°-70° C.
Reaction SMILES: [I:1]I.Br[C:4]1[C:18]2=[C:19]3[C:7]([N:8]([Si](C(C)(C)C)(C)C)[CH:9]=[C:10]3[CH2:11][C@@H:12]3[C:17]2=[CH:16][C@H:15]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:14][N:13]3[CH3:28])=[CH:6][CH:5]=1>>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([NH:20][C@H:15]1[CH2:16][C@H:17]2[C@@H:12]([CH2:11][CH:10]3[C:19]4[C:7](=[CH:6][C:5]([I:1])=[CH:4][C:18]2=4)[NH:8][CH2:9]3)[N:13]([CH3:28])[CH2:14]1)=[O:27])[CH3:24]
Reactant: II
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3c(Br)ccc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(I)cc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
With iodine and 3-(12-bromo-1-tert-butyldimethylsilyl9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[C:18](O)=[C:17]([F:20])[C:16]([F:21])=[CH:15][CH:14]=1>O.[OH-].[Na+].ClCCl>[Br:11][C:5]1[CH:6]=[C:7]([C:8]2[O:10][C:18]3[C:17]([F:20])=[C:16]([F:21])[CH:15]=[CH:14][C:13]=3[N:12]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ccc(F)c(F)c1O
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Nc1ncc(Br)cc1-c1nc2ccc(F)c(F)c2o1
Temperature: 200 °C
Yield: 22.5 %

Procedure:
To a mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g) and 6-amino-2,3-difluoro-phenol (0.669 g) placed in a round bottom flask was added polyphosphoric acid (10 g). The mixture was heated at 200° C. for 5 hours. A homogenous black mixture was obtained. The mixture was diluted in water and neutralizing to pH 8 with NaOH 2N. The heterogeneous mixture was diluted with dichloromethane. The insoluble was filtered. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried on sodium sulfate, evaporated and dried to afford 5-bromo-3-(6,7-difluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (0.338 g). NMR Spectrum: (DMSOd6) 7.54 (ddd, 1H), 7.70 (ddd, 1H), 7.79 (bs, 2H), 8.34 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 326-328
Reaction SMILES: O[CH:2]([CH:12]([CH3:14])[CH3:13])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[CH3:13][CH:12]([CH3:14])/[CH:2]=[CH:3]/[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)C(O)CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)/C=C/C(=O)c1ccccc1
Yield: 91.1 %

Procedure:
A mixture of 3-hydroxy-4-methyl-1-phenyl-1-pentanone (8.400 gm, 43.7 mmol) and p-toluenesulfonic acid (820 mg, 4.3 mmol) in benzene (210 ml) was refluxed in a Dean-Stark apparatus for 10 minutes. The solution was cooled, diluted with Et2O, and washed with saturated NaHCO3 and brine. Filtration and removal of the solvent afforded a yellow oil which was subsequently distilled (P=2.0 mm, 97°-100° C.) to give the (E)-4-methyl-1-phenyl-2-penten-1-one (6.94 gm) as a colorless liquid. 1H-NMR analysis showed the distillate to be 78% the desired product and 22% the β, δ-unsaturated isomer. The material was used directly for the next reaction.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([CH3:7])[NH2:6])=[O:4].[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:19][C:20]1[N:24]2[N:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1>>[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:19][C:20]1[N:24]2[N:25]=[C:26](/[C:29](=[N:6]/[N:5]([CH3:7])[C:3]([NH:2][CH3:1])=[O:4])/[CH3:30])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: CNC(=O)N(C)N
Product: CNC(=O)N(C)/N=C(\C)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 21 %

Procedure:
The title compound was prepared from N,1-dimethylhydrazine carboxamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 21% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (dd, 1H), 8.31 (d, 1H), 8.06 (m, 2H), 7.97 (d, 1H), 7.77 (d, 1H), 7.73 (s, 1H), 7.47 (q, 1H), 6.90 (q, 1H), 4.59 (s, 2H), 3.19 (s, 3H), 2.68 (d, 3H), 2.37 (s, 3H). LCMS (method B): [MH]+=406, tR=2.27 min.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[S:19][C:17]=2[N:18]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine gives 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [CH3:1][C:2]([NH2:15])([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH3:14][C:2]([NH:15][C:16](=[O:18])[CH3:17])([CH3:1])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: Cc1ccc2c(CC(C)(C)N)c[nH]c2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)(C)Cc1c[nH]c2cc(C)ccc12
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A solution of 1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethylamine (2 mmole, prepared according to Lit. 2) and acetic anhydride (2.2 mmole) in dichloromethane (3 ml) was treated with triethylamine (6 mmole) and the mixture was stirred at 22° C. for 18 h. The mixture was washed with aqueous hydrochloric acid (1N), the organic layer was dried and evaporated to give N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-acetamide as a brownish solid. MS: 243.2 ([M−H]−).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH2:17][CH2:18][O:19][C:20]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][C:21]=4[CH:22]=3)=[O:15])=[CH:9][CH:8]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:42][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH2:17][CH2:18][O:19][C:20]4[CH:26]=[CH:25][C:24]([C:27]5[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=5)=[CH:23][C:21]=4[CH:22]=3)=[O:15])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4cccnc4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4ccc[n+]([O-])c4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 68 h
Yield: 52.1 %

Procedure:
To a solution of N-[4-(3-pyridyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (400 mg) in tetrahydrofuran (50 ml) was added 3-chloroperbenzoic acid (70%, 0.34g) at 0° C., and the mixture was stirred at room temperature for 68 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:1), and recrystallized from ethanol-chloroform to give N-[4-(1-oxidopyridin-3-yl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 165) (216 mg) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=O)[O:30][CH:31]([CH2:32][CH3:33])[C:25]=2[CH:24]=1.Cl>C1COCC1>[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[O:30][CH:31]([CH2:32][CH3:33])[C:25]=2[CH:24]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCC1OC(=O)c2cnc(Cl)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (4.71 g, 31.2 mmol.) in THF (30 mL) is cooled to 0° C. under an argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (60 mL of a 1 M solution in THF, 60.0 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed room temperature. A solution of 6-chloro-1-ethyl-1H-furo[3,4-c]pyridin-3-one, (4.11 g, 20.8 mmol) in THF (30 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (350 mL). The resulting mixture is heated to 90° C. for 2 h and then stirred at room temperature for 36 h. The precipitate which forms is collected by filtration and washed with small volumes of ethyl acetate (10×3 mL) and dried to give the title compound as a yellow solid (2.37 g, 34%).