Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[N:11]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([Br:24])[C:21]=1[O:22][CH3:23])[C:16](Cl)=[O:17].C(N(CC)CC)C.O>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C:16]([N:10]2[CH2:9][CH2:8][O:7][C:6]3[N:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=3)=[O:17])[CH:19]=[C:20]([Br:24])[C:21]=1[O:22][CH3:23]
Reactant: Cc1ccc2c(n1)OCCN2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1c(Br)cc(C(=O)N2CCOc3nc(C)ccc32)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 ml flask, 6-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (110 mg, 0.73 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (240 mg, 0.73 mmol) were dissolved in dichloromethane (5 ml). Triethylamine (0.26 ml, 1.8 mmol) was added thereto and then stirred at room temperature for 1 hour. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica (NH-silica gel) eluting with a solvent of dichloromethane:methanol=19:1. The fractions containing the product were collected and evaporated to obtain the target compound 58, i.e., (3,5-dibromo-4-methoxy-phenyl)-(6-methyl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone, as white solid (230 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[N:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C@H:37]([C:48](O)=[O:49])[CH2:38][C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1COCC1.C([O-])([O-])=O.[K+].[K+].Cl>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:36][C@H:37]([C:48]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@H:4]([N:5]([S:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:16][CH:17]([CH3:18])[CH3:19])[C:3]([O:2][CH3:1])=[O:25])=[O:49])[CH2:38][C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: COC(=O)[C@H](CCCCN)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(C)cc1)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine methyl ester (369 mg, 1 mmol, example 65, step C) in THF/K2CO3 (1M) (3 mL/3 mL) was added Nα-(4-methylbenzenesulfonyl)-L-tryptophan N-hydroxysuccininide ester (547 mg, 1.2 mmol). The reaction mixture was stirred overnight, then diluted with 1N HCl and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The crude was purified by flash chromatography using hexane/EtOAc as eluent to afford the desired product (71% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[CH:21][N:22]=[C:23](I)[N:16]3[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1C=CC=[CH:34][CH:33]=1>C(#N)C>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[CH:21][N:22]=[C:23]([CH:32]4[CH2:31][CH2:25][O:28][CH2:34][CH2:33]4)[N:16]3[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CC1CN(Cc2ccccc2)CC1c1nn2c(I)ncc2c(=O)[nH]1
Agent: [K+]
Solvent: CC#N
Product: CC1CN(Cc2ccccc2)CC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
To a solution of compound 6 (70 mg, 0.296 mmol) and potassium carbonate (70 mg, 0.296 mmol) in acetonitrile (10 mL) was added benzyl bromide (70 mg, 0.296 mmol). The resulting solution was stirred at room temperature for 2 h. LC-MS showed that the reaction was complete. The reaction was quenched with water (40 mL), and the reaction mixture was extracted with CH2Cl2 (30 mL×3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by preparative TLC (CH2Cl2/MeOH=10:1) to afford the desired product (28.6 mg, 25% yield) as a white solid. LC-MS: m/z 394.2 [M+1]+. 1H NMR (400 MHz, CD3OD-d4): δ 7.60 (s, 1H), 7.29˜7.22 (m, 4H), 7.19˜7.17 (m, 1H), 3.95˜3.92 (m, 2H), 3.69˜3.58 (m, 2H), 3.52˜3.46 (m, 3H), 3.21 (m, 1H), 3.06˜3.04 (m, 1H), 2.91˜2.76 (m, 2H), 2.58˜2.56 (m, 1H), 2.16 (m, 1H), 1.89˜1.81 (m, 2H), 1.78 (m, 2H), 1.27 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([C@@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:34]([O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])=[CH:33][C:17]=1[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[C:2]([C:6]1[CH:7]=[C:8]([C@@H:12]([NH:14][C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][C:17]2[CH:33]=[C:34]([CH:35]=[CH:36][C:16]=2[Cl:15])[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:20]([CH3:32])=[C:21]3[CH3:31])=[O:29])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H](N)c1cccc(C(C)(C)C)c1
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride the (S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.Cl[CH2:22][C:23]#[N:24]>C(N(CC)CC)C>[OH:15][C@H:10]1[C@H:9]([NH:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:14][CH2:13][N:12]([CH2:22][C:23]#[N:24])[CH2:11]1
Reactant: O[C@@H]1CNCC[C@H]1NCc1ccccc1
Reactant: N#CCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCN1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred and heated (±70° C.) solution of 14.44 parts of trans-4-[(phenylmethyl)amino]-3-piperidinol in 189 parts of N,N-dimethylformamide were added 5.81 parts of chloroacetonitrile. After the addition of 9.7 parts of N,N-diethylethanamine, stirring was continued overnight at 70° C. After evaporation, the residue was taken up in dichloromethane. The organic layer was washed with a sodium carbonate solution in water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 13.1 parts (76.2%) of trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidineacetonitrile; mp. 113.2° C. (interm. 16).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH2:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CBr
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 126 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-bromo-2-methylpropane and conditions outlined in procedure V. M.p.=158-161° C.; 400 MHz 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 2.9 (s, 2H), 2.75 (d, 2H), 2.4 (t, 2H), 2.15 (d, 2H), 2.1 (d, 2H), 1.75-1.9 (m, 3H), 0.9 (s, 6H); LCMS: 358 [M+H].
Reaction SMILES: CO[CH:3]=[C:4]([C:15]#[N:16])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:18][C:19]([NH2:21])=[NH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:21][C:19]1[N:20]=[C:15]([NH2:16])[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][N:18]=1
Reactant: N=C(N)N
Reactant: COC=C(C#N)CCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(CCCCc2ccccc2)c(N)n1
Yield: 52.5 %

Procedure:
A stirred solution of 2.4 grams (0.011 mole) of 1-methoxy-2-cyano-6-phenyl-1-hexene, 4.2 grams (0.044 mole) of guanidine hydrochloride, and 7.6 grams (0.055 mole) of potassium carbonate in 40 mL of N,N-dimethylformamide was heated at 100° C. to 105° C. for about 20 hours. After this time the reaction mixture was diluted with 100 mL of water. The mixture was then extracted with two 100 mL portions of ethyl acetate. The combined extracts were washed with three 75 mL portions of an aqueous 10% lithium chloride solution. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The residue was subjected to column chromatography on basic alumina that was deactivated to Level III with water. Elution was accomplished with 1% to 3% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.4 grams of 2,4-diamino-5-(4-phenylbutyl)pyrimidine; mp 126°-127° C. The NMR spectrum was consistent with the proposed product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:13]C(=O)C)[CH2:10][C@H:9]1[CH2:17][N:18]1C(=O)C2=CC=CC=C2C1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([SH:13])[CH2:10][C@H:9]1[CH2:17][NH2:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OC(C)(C)C)C1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](S)C[C@H]1CN
Yield: 83.2 %

Procedure:
To a solution of (2S,4S)-1-t-butoxycarbonyl-2-phthalimidomethyl-4-acetylthiopyrrolidine (8.58 g) in a mixture of dichloromethane (26 ml) and methanol (129 ml), hydrazine hydrate (4.11 ml) is added. The mixture is heated to reflux for 2 hours and 45 minutes and filtered. The filtrate is concentrated in vacuo. The residue is dissolved in dichloromethane, washed with water, dried over sodium sulfate, and concentrated in vacuo to give crude (2S,4S)-1-t-butoxycarbonyl-2-aminomethyl-4-mercaptopyrrolidine (4.1 g). Yellow syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:10][N:11]([CH3:36])[C:12]([C:14]1[N:19]=[CH:18][C:17]([O:20][C:21]2[C:26]3[CH:27]=[C:28]([CH3:30])[O:29][C:25]=3[CH:24]=[C:23]([C:31](OCC)=[O:32])[CH:22]=2)=[CH:16][N:15]=1)=[O:13]>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:31]([C:23]2[CH:22]=[C:21]([O:20][C:17]3[CH:18]=[N:19][C:14]([C:12]([N:11]([CH3:10])[CH3:36])=[O:13])=[N:15][CH:16]=3)[C:26]3[CH:27]=[C:28]([CH3:30])[O:29][C:25]=3[CH:24]=2)=[O:32])=[N:7][CH:8]=1
Reactant: COc1cnc(N)cn1
Reactant: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Product: COc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)nc3)c3cc(C)oc3c2)cn1

Procedure:
The title compound (3) was prepared by a method analogous to that described in Example 1 using 5-methoxypyrazin-2-amine and ethyl 4-(2-(dimethylcarbamoyl)-pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-2a).
Reaction SMILES: C([O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][O:18]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[ClH:27].C(ONCCCCCCNOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+].Cl>C(O)C.O>[ClH:27].[OH:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][OH:18]
Reactant: O=C(ONCCCCCCNOC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ONCCCCCCNO
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
The specific laboratory procedure for carrying out the above reaction scheme is as follows. Benzoyloxy peroxide (24.2 g, 0.1 mol) is dissolved in 300 ml of absolute benzene. Then, 1,6-diaminohexane (1) (11.6 g, 0.1 mol) dissolved to 100 ml of absolute ether is added to the benzoyloxy peroxide-benzene solution dropwise. The reaction mixture is kept while stirring at 40°-50° C. for two hours. 100 ml of absolute ether is added and the resultant precipitate is separated. Then, dry HCl gas is passed through the solution to form 1,6-dibenzoyloxy amino hexane hydrochloride (3), (M.W. 429, M.P. 137°-138° C.), which is recrystallized in absolute ethanol (yield 45%). 1,6-dibenzoyloxy amino hexane (2) is formed by treating (3) with 10% NaHCO3 solution. (M.W. 356, M.P. 70° C.). Then the purified product (3) (6.45 g, 0.015 mol) is dissolved in 200 ml of absolute ethanol. 150 ml of concentrated HCl solution is added slowly and the mixture refluxed for one and a half hour at 85° to 95° C. The refluxing is stopped and the reaction mixture cooled to about 30° C. using an ice bath. Then 150 ml of distilled water is added and stirred for another half hour at 30° C. The entire solvent is evaporated with a rotary evaporator. The residue is then dissolved into an isopropanol-ethylacetate mixture for crystallization. Further, recrystallization is carried out in the same solvent system. The resulting white powder-like crystal is 1,6-dihydroxylamino hexane hydrochloride (4) (M.W. 221, M.P. 135° C.). The yield is 56%. The free base form of (4), 1,6-dihydroxylamine hexane (5) can be obtained by treating (4) with mild base, such as NaHCO3 solution.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[C:44]3[CH:45]=[C:46]([Cl:49])[CH:47]=[CH:48][C:43]=3[S:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[C:44]3[CH:45]=[C:46]([Cl:49])[CH:47]=[CH:48][C:43]=3[S:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2csc3ccc(Cl)cc23)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2csc3ccc(Cl)cc23)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.62 g), sodium hydrogen carbonate (2.6 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[(5-chloro-1-benzothien-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.82 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.30 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.58 g, 62%).
Reaction SMILES: [OH:1][Li].O.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:17][C:14]3([CH2:16][CH2:15]3)[N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2=[O:25])=[CH:7][CH:6]=1>O.CO.C1COCC1>[C:21]([O:20][C:18]([NH:13][C:14]1([CH2:17][CH:11]([C:8]2[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=2)[C:12]([OH:25])=[O:1])[CH2:16][CH2:15]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(c2ccc(Cl)cc2)CC12CC2
Reactant: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CC(C(=O)O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A solution of LiOH hydrate (0.24 g, 5.7 mmol) in water (2 mL) was added to a stirred solution of tert-butyl 6-(4-chlorophenyl)-5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (0.46 g, 1.4 mmol) in MeOH (2 mL) and THF (2 mL). The reaction was stirred at room temperature overnight. The solvents were evaporated in vacuo. The residue was taken up in water and extracted with ether (2×). The aqueous phase was acidified by 2N HCl and extracted with EtOAc. The combined organic phases were washed with brine, dried and concentrated to give 3-(1-(tert-butoxycarbonylamino)cyclopropyl)-2-(4-chlorophenyl)propanoic acid (0.41 g, 84%) as a white solid. LCMS (APCI+) [M-Boc+H]+ 240.0; Rf: 2.38 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][O:39][CH3:40]>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:37][CH2:38][O:39][CH3:40])[CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COCCBr
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCCN1CCC(COc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]quinazoline (Example 3, 104 mg, 0.25 mmol) was dissolved in DMA (5 ml). Potassium carbonate (138 mg, 1.00 mmol) and 1-bromo-2-methoxyethane (24 μl, 0.25 mmol) were added. The mixture was stirred at 60° C. for 4 hours. Further potassium carbonate (138 mg, 1.00 mmol) and 1-bromo-2-methoxyethane (24 μl, 0.25 mmol) were added; heating was continued at 60° C. for a further 4 hours. The solvent was evaporated and the residue was partitioned between DCM (20 ml) and water (20 ml). The aqueous layer was extracted with DCM (2×10 ml) and the extractions combined with the DCM layer. The combined DCM fractions were filtered through a silicone-treated filter paper and evaporated. The residue was purified by chromatography, eluting with 0 to 2.5% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, and the crude product (40 mg) re-dissolved in 1:1 methanol/DCM (5 ml). Ethereal HCl (1M, 0.5 ml) was added, and the mixture evaporated. Crystallisation from iso-propanol/diethyl ether gave the title product as a hydrochloride salt, a yellow solid (28 mg, 20%); 1H NMR (hydrochloride salt): 1.60-1.75 (m, 2H), 2.00-2.05 (m, 2H), 2.16 (m, 1H), 2.95-3.10 (m, 2H), 3.22 (t, 2H), 3.29 (s, 3H), 3.50-3.57 (m, 2H), 3.70 (t, 2H), 3.99 (s, 3H), 4.12 (d, 2H), 7.34 (dd, 1H), 7.39 (s, 1H), 7.51 (dd, 1H), 7.61 (dd, 1H), 8.46 (s, 1H), 8.78 (s, 1H), 10.08 (br. s, 1H); Mass Spectrum: 475.5, 477
Reaction SMILES: Cl[NH:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[NH:22]([CH2:24][C:25](O)=O)[CH3:23].[OH-:28].[Na+]>O>[CH2:24]([NH:22][C:23]([NH:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:28])[CH2:25][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCl
Reactant: [OH-]
Reactant: CNCC(=O)O
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCNC(=O)NC(=O)CCCCCCCCCCCCCCCCC

Procedure:
In accordance with the procedures described in Example 19, 31.75 g (0.1 mol) stearic N-chloramide was reacted with sarcosine/sodium hydroxide in water to yield 88% by weight of N-n-heptadecyl-N'-stearoyl urea of the formula ##STR20## having a melting point of 110° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:12]1([C:15]2[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[C:16]([N:24]3[CH2:25][CH2:26][N:27]([C:6]([C:5]4[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=4[CH3:11])=[O:8])[CH2:28][CH2:29]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:13][CH2:14]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: Cc1cc(F)ncc1C(=O)O
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 85.5 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (0.60 g) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (0.92 g) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.23 g) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:17][C:11]=2[N:10]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C(N(CC)CC)C>ClCCl>[NH2:8][C:9]1[N:10]([C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Reactant: O=C(Cl)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2n1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.53 g of 4-fluoro-benzenesulfonic acid 2-amino-1H-benzoimidazol-5-yl ester trifluoroacetic acid salt were combinated with 1.8 ml of cyclopropanecarbonylchloride and 5 ml triethylamine in 75 ml dichloromethane. Reaction mixture was stirred at room temperature for 1 hour. Solvents were evaporated under reduced pressure. The residue was then taken up in dichloromethane, washed with water and dried with magnesium sulfate. Dichloromethane was evaporated under reduced pressure and precipitate obtained was dried on glass frit yielding 4.88 g of 4-fluoro-benzenesulfonic acid 2-amino-3-cyclopropanecarbonyl-3H-benzoimidazol-5-yl ester.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:24][C@H:21]2[CH2:22][CH2:23][C@H:18]([O:17][CH3:16])[CH2:19][CH2:20]2)[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Reactant: CO[C@H]1CC[C@H](N)CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CNc1ncc(Br)nc1N[C@H]1CC[C@H](OC)CC1
Temperature: 150 °C

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (30.0 g, 88 mmol), trans-4-methoxycyclohexanamine (17.15 g, 133 mmol), N,N-diisopropylethylamine (30.8 mL, 177 mmol) and dimethylsulfoxide (70.8 mL) were combined in a reaction vial with a stirbar and heated in an oil bath at 150° C. for 16 h with stirring. The resulting mixture was diluted with ethyl acetate and the volatiles removed under reduced pressure. The residue was purified using silica gel chromatography on a Biotage SP1 (12% ethyl acetate in hexanes). Fractions containing the desired product were combined and organic volatiles removed under reduced pressure. The residue was triturated with 5% ethyl acetate in hexane. Solids were collected by vacuum filtration, washed with hexane and dried under vacuum to afford ethyl the title compound (15.37 g, 39.7 mmol, 44.8% yield) as an off-white solid. MS (ESI) m/z 387.0 [M]+, 389.0 [M+2]+.