Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29]N>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[F:22])[N:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(Cl)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(Cl)cc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 1-(4-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-24) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=367.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]([CH3:40])[N:37]=[CH:38][CH:39]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]([CH3:40])[N:37]=[CH:38][CH:39]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnn3C)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K7) (180 mg, 0.6 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (160 mg).
Reaction SMILES: [S:1](S([O-])=O)([O-:4])(=[O:3])=[O:2].[Na+:8].[Na+].[S:10]([O-:13])([O-:12])=[O:11].[Na+].[Na+].[H][H]>O>[S:1]([O-:4])([O-:3])=[O:2].[Na+:8].[Na+:8].[S:10](=[O:11])([OH:13])[O-:12]
Reactant: [H][H]
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])O

Procedure:
An aqueous solution of sodium sulfite and bisulfite was prepared by mixing 38.8 lbs of sodium metabisulfite and 17.0 lbs of sodium sulfite with 88.2 lbs of water. The salt solution was metered into the recycle loop at a rate of 7.6 lbs per hour. Simultaneously a glyceryl epoxide wherein R is normal alkyl of 12 to 15 carbon atoms, R' is hydrogen and n is average value of 1 according to Formula 1 was metered into the recycle loop at a rate of 10.0 lbs/hour. The recycle loops residence time was thirty minutes. At steady state, the temperature maintained in the recycle loop was 160° C. and the pressure was 100 psig. The residence times were varied in sequential runs by increasing the metering rates of the reactants proportionately to achieve residence times of 15, 10 and 5 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8](COCCOC)[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH2:21][C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].Cl>CO>[Cl:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH2:21][C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2C)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1cc2c(cc1Cc1sc3ncccc3c1S(=O)(=O)Nc1noc(C)c1Cl)OCO2
Yield: 83.7 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-5-methyl-3-isoxazolyl)-N-(methoxyethoxymethyl)-2-[2-methyl-4,5 -(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (58 mg, 0.10 mmoles), methanol (3 ml) and 4N HCl (1 ml). Recrystallization from chloroform and hexanes provided 40 mg (80%) of the title compound as a white solid, m.p. 189-191° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8](I)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1CCc2cccc(I)c2C1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1CCc2cccc(C#C[Si](C)(C)C)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(Di-n-propylamino)-8-iodo-1,2,3,4-tetrahydronaphthalene (4.3 g, 12.1 mmol), as prepared in co-pending U.S. application Ser. No. 07/653,583 triethylamine (100 ml) was added copper(I) iodide (228 mg), bis(triphenylphosphine)-palladium(II) chloride (841 mg) and trimethylsilylacetylene (1.7 ml). This mixture was stirred at room temperature overnight. The reaction was poured into water and extracted with ether. The extract was washed with brine, dried (Na2SO4), and concentrated to give 5 g of crude product. Purification by flash chromatography using 20:1 methylene chloride:methanol as solvent gave 4.33 g of 2-(di-n-propylamino)-8-(2-trimethylsilylethynyl)-1,2,3,4-tetrahydronaphthalene which was used in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)=[O:17])[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[NH3:30]>CO>[NH2:30][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:6]([CH3:13])=[CH:5][C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)=[O:17])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1OCC1CO1
Reactant: N
Solvent: CO
Product: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1OCC(O)CN

Procedure:
A solution of 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (30 mg, 74 μmol) in methanol (1 mL) and ammonia (22 μL, approx. 7 N solution in methanol) is stirred at 65° C. for 4 h and at rt for 18 h. The solvent is removed in vacuo and the residue is purified by prep. HPLC to give 3-[4-(3-amino-2-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (4 mg) as a colourless resin; LC-MS: tR=0.87 min, [M+1]+=424.24.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:8]([O:10]C)=O)[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[NH2:22][C@H:23]([C:25]([NH:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29])=[O:26])[CH3:24]>>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:8]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29])=[O:26])[CH3:24])=[O:10])[CH2:3][CH2:4][C:5](=[O:7])[OH:6]
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
0.2 ml of aqueous solution containing 2 mM Z-Glu-OMe, 50 mMH-Ala-Ala-OH, 25 mMNaOH and 5 mg/ml endoproteinase Glu-C are deep-frozen. Subsequently the reaction mixture is kept at -25° C. until the Z-Glu-OMe is consumed. Following thawing, the yield is determined analytically by RP-HPLC and amounts to 76% of theory.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[N:7]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[CH3:17][O:18][C:19]([C@H:21]1[CH2:26][C@H:25]([NH2:27])[CH2:24][CH2:23][N:22]1C(OC(C)(C)C)=O)=[O:20]>>[CH3:17][O:18][C:19]([C@H:21]1[CH2:26][C@H:25]([NH:27][C:8]2[N:7]=[C:6]([C:5]3[S:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[CH:4]=3)[CH:11]=[CH:10][N:9]=2)[CH2:24][CH2:23][NH:22]1)=[O:20]
Reactant: COC(=O)[C@H]1C[C@H](N)CCN1C(=O)OC(C)(C)C
Reactant: Clc1nccc(-c2cc3ccccc3s2)n1
Product: COC(=O)[C@H]1C[C@H](Nc2nccc(-c3cc4ccccc4s3)n2)CCN1

Procedure:
The title compound was prepared from 4-benzo[b]thiophen-2-yl-2-chloro-pyrimidine and (2R,4R)-4-amino-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester according to Step C of Method A. Yield 45 mg (45%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:16])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:16][C:4]3[C:5]([C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
5,6,5′-Trimethyl-[2,2′]bipyridin-3-ol (300 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.26 g), 4-dimethylaminopyridine (513 mg), and cesium carbonate (1.37 g) were suspended in dimethyl sulfoxide (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (504 mg, yield 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=1)[N:6]=[CH:5]2.[C:21](=[NH:35])(SCC1C=CC2C(=CC=CC=2)C=1)[CH3:22]>C(O)C>[O:18]1[C:15]2[CH:16]=[CH:17][C:12]([C:7]3[N:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:21](=[NH:35])[CH3:22])[CH:3]=4)[N:8]=3)=[CH:13][C:14]=2[O:20][CH2:19]1
Reactant: Nc1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Reactant: CC(=N)SCc1ccc2ccccc2c1
Solvent: CCO
Product: CC(=N)Nc1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
A suspension in ethanol (80 ml) of 6-amino-2-(3,4-methylendi-oxy-phenyl)-quinazoline (5 g, 0.019 mol) and S-2-naphthylmethyl thioacetimidate bromidrate (5.63 g, 0.019 mol, prepared as described in Tetrahedron Letters 38, 179-182 (1997), was stirred at r.t. for 24 hrs. Then S-2-naphthylmethyl thioacetimidate bromidrate (2.8 g, 0.010 mol) was added and the mixture was stirred at r.t. for further 24 hrs., then was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was basified with Na2CO3 and extracted with ethyl acetate. The product was extracted with aqueous HCl (0.001 N) for three times. The aqueous layers were collected, basified with Na2CO3 and extracted with ethyl acetate. The organic layer was washed with water and dried over Na2SO4, concentrated under reduced pressure, and then the residue was triturated with diethyl ether. The yellow solid was filtered and dried in vacuum to give the titled product (2.4 g, 42% yield).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[F:19][C:18]([F:20])([F:21])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[O:30])=[CH:9][CH:10]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:37]2[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 552.2 [M−H]−.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([OH:22])([C:20]#[N:21])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-:23].[Na+]>O>[CH2:7]([N:14]1[CH2:15][CH2:16][C:17]([OH:22])([C:20]([NH2:21])=[O:23])[CH2:18][CH2:19]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixed solution of 18 ml conc. sulfuric acid and 1.8 ml water was cooled to 0° C., and 5 g of 1-benzyl-4-hydroxy-4-piperidinecarbonitrile hydrochloride was added thereto little by little. A mixed solution of 25 ml conc. sulfuric acid and 2.5 ml water was added thereto, and stirred at room temperature for 2 hr. It was left overnight in a freezer. The reaction solution was poured onto ice, and 47 g of sodium hydroxide was added thereto little by little. It was extracted 3 times with a mixed solvent of tetrahydrofuran and ethyl acetate (1:1). The extract was washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated and subjected to silica gel column chromatography to give 3.19 g of 1-benzyl-4-hydroxy-4-piperidine carboxamide.
Reaction SMILES: [FH:1].F.F.C(N(CC)CC)C.C(N(CC)CC)C.[CH2:18]([O:20][C:21]([CH:23]1[CH2:26][C:25](O)([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH2:37][C:36]([C:42]4[CH:47]=[C:46]([Cl:48])[C:45]([Cl:49])=[C:44]([Cl:50])[CH:43]=4)([C:38]([F:41])([F:40])[F:39])[O:35][N:34]=3)=[CH:29][CH:28]=2)[CH2:24]1)=[O:22])[CH3:19]>C(Cl)Cl>[CH2:18]([O:20][C:21]([CH:23]1[CH2:24][C:25]([F:1])([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH2:37][C:36]([C:42]4[CH:43]=[C:44]([Cl:50])[C:45]([Cl:49])=[C:46]([Cl:48])[CH:47]=4)([C:38]([F:40])([F:41])[F:39])[O:35][N:34]=3)=[CH:29][CH:28]=2)[CH2:26]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of triethyl amine trihydrofluoride (4.21 g, 26.16 mmol, 4 eq.) in DCM (25 mL) was added triethyl amine (1.32 g, 13.08 mmol) in drop wise manner at −78° C. After 15 minutes was added X-TalFluoro-M (4.74 g, 19.62 mmol) followed by addition of pre-dissolved solution of 3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid ethyl ester (Preparation 3, 3.5 g, 6.54 mmol) in DCM (15 mL) at −78° C. Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material, reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate (50 mL) and stirred at room temperature for 0.5 hours. Aqueous layer was extracted with DCM (3×50 mL). Combined organic layers were dried over sodium sulphate, filtered and evaporated. Purification was done by column chromatography on silica gel (100-200 mesh size). Compounds were eluted using 5% ethyl acetate in hexane to afford two off-white solids (2 g-non-polar spot, and 1.2 g-polar spot). 1H NMR (400 MHz, CDCl3) (Non Polar spot) δ: 1.26 (t, J=7.12 Hz, 3H), 2.80 (d, J=8.76 Hz, 2H), 2.87 (d, J=8.72 Hz, 2H), 3.47-3.49 (m, 1H), 3.67 (d, J=17.16 Hz, 1H), 4.08 (d, J=17.16 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 7.51 (d, J=8.12 Hz, 2H), 7.63 (s, 2H), 7.67 (d, J=8.16 Hz, 2H); LC-MS (m/z): 536.00 (M−H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:33][CH2:32][C:12]3([CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:13]3)[CH2:11][CH2:10]2)[N:3]=1.[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH2:44][NH2:45].CCN(CC)CC>C(O)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:45][CH2:44][C:35]2[CH:36]=[CH:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]=2)[N:5]=[C:4]([N:9]2[CH2:33][CH2:32][C:12]3([CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:13]3)[CH2:11][CH2:10]2)[N:3]=1
Reactant: NCc1ccc2ccccc2c1
Reactant: CCOC(=O)C1CC2(CCN(c3nc(N)nc(Cl)n3)CC2)CN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)C1CC2(CCN(c3nc(N)nc(NCc4ccc5ccccc5c4)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-benzyl 3-ethyl 8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (265 mg, 0.56 mmol) in isopropanol (3 mL) were added naphthalen-2-ylmethanamine (105 mg, 0.67 mmol) and Et3N (1.4 mL). The reaction mixture was heated to reflux for 12 h, then cooled to RT, and concentrated in vacuo. Purification by normal phase chromatography (CH2Cl2/MeOH) provided 2-benzyl 3-ethyl 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH2:36]([N:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][NH2:44])[CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[CH2:36]([N:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][NH:44][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:35])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: CCCCN(CCCC)CCCN
Solvent: ClCCl
Product: CCCCN(CCCC)CCCNc1nc(-c2cc(C(=O)NCCC)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 80.4 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (30 mg, 0.06 mmol) in DCM (5 mL) was added N,N-dibutyl-1,3-propanediamine (0.06 mL, 0.26 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (30 mg, 83%). LC-MS m/z 622 (M+H)+; 1H-NMR (MeOD) δ 1.00 (m, 10H), 1.30 (m, 4H), 1.50 (m, 9H), 2.31 (s, 3H), 2.38 (m, 4H), 2.48 (m, 2H), 3.08 (m, 2H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18][C:19]2[N:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH2:13]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]1([C:7]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18][C:19]3[N:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=3)[CH2:13]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCNC2)nc1
Reactant: O=C(O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCN(C(=O)C3CCCCC3)C2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of cyclohexanecarboxylic acid (133 mg, 1.03 mmol), ethyl (2E)-3-{6-[(3R)-3-piperidinylamino]-3-pyridinyl}acrylate dihydrochloride (300 mg, 0.86 mmol), HOBt (163 mg, 1.21 mmol) and EDCI (174 mg, 1.12 mmol) in DMF (6 mL) was stirred at 0° C. for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (hexane-EtOAc=1-1) to give ethyl (2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate (313 mg, 94%) as an amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[N:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:11].Br[CH2:20]Cl.C([Li])CCC>CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:10]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH2:20][O:18]1
Reactant: CC(C(=O)c1ccc(F)cc1F)c1cccnn1
Reactant: ClCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(c1cccnn1)C1(c2ccc(F)cc2F)CO1
Yield: 56.8 %

Procedure:
Treatment of the product of part (ii) (2.0 g) with bromochloromethane (1.15 g) and n-butyllithium (5.28 ml of a 1.6M solution in hexane) according to the method of Example 11(iii) gave the title compound as a gum (1.20 g) which was used directly in the next stage.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[S:4]
Reactant: CC(=O)NCCCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)NCCCC(=NNC(N)=S)c1ccccc1
Yield: 60.7 %

Procedure:
Thiosemicarbazide (2.85 g, 31.3 mmol) was added to a solution of N-(4-oxo-4-phenyl-butyl)-acetamide (4.28 g, 20.9 mmol), prepared in the previous step, in 75 ml of methanol plus 5.6 ml of 1 N HCl, plus 5.6 ml of water and the reaction stirred at room temperature for 42 hours. The reaction was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, washed five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 4.77 g of a yellow solid Recrystallization of this solid from ethyl acetate gave the title compound (3.53 g, 61%) as an off-white solid, mp 74-83° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[O:23])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[ClH:32].O1CCOCC1>ClCCl>[ClH:32].[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COCC(N)=N1
Temperature: 40 °C

Procedure:
A solution of (5-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (44.4 mg, 0.1 mmol) in dichloromethane was treated with 4M HCl in dioxane (40 eq). The mixture was warmed to 40° C. for 10 h and then evaporated under reduced pressure to yield the title compound (hydrochloride salt) in the form of a colourless solid. 1H-NMR (500 MHz, DMSO-d6): 10.70 (s, 1H), 10.62 (s, 1H), 9.14 (s, 1H), 8.87 (d, 1H), 8.52 (s, 1H), 8.34 (dd, 1H), 8.11 (d, 1H), 7.96 (m, 2H), 7.43 (t, 1H), 7.21 (d, 1H), 4.59 (s, 2H), 3.88 (m, 2H), 1.65 (s, 3H); MS: 389 [(M+H)+].