Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:16]([F:17])=[CH:15][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][O:10][CH2:9][C@@H:8]2[CH3:14])=[C:4]([F:18])[CH:3]=1.[F:19][C:20]1[C:21]([C:27]2[N:31]([CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:30]([CH3:38])=[N:29][CH:28]=2)=[N:22][C:23]([NH2:26])=[N:24][CH:25]=1.CC(C)([O-])C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CN(C=O)C.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][C@@H:12]1[N:7]([CH2:6][C:5]2[C:4]([F:18])=[CH:3][C:2]([NH:26][C:23]3[N:22]=[C:21]([C:27]4[N:31]([CH:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[C:30]([CH3:38])=[N:29][CH:28]=4)[C:20]([F:19])=[CH:25][N:24]=3)=[C:16]([F:17])[CH:15]=2)[C@@H:8]([CH3:14])[CH2:9][O:10][CH2:11]1
Reactant: Cc1ncc(-c2nc(N)ncc2F)n1C1CCOCC1
Reactant: C[C@H]1COC[C@H](C)N1Cc1cc(F)c(Cl)cc1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ncc(-c2nc(Nc3cc(F)c(CN4[C@@H](C)COC[C@@H]4C)cc3F)ncc2F)n1C1CCOCC1
Temperature: 120 °C
Yield: 7.2 %

Procedure:
(3S,5S)-4-(4-Chloro-2,5-difluorobenzyl)-3,5-dimethylmorpholine (0.118 g, 0.43 mmol), 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.142 g, 0.51 mmol) and potassium tert-butoxide (0.058 g, 0.51 mmol) were mixed in dioxane (2 mL) and DMF (0.5 mL). Argon was bubbled through the mixture for 2 minutes. Pd2(dba)3 (0.047 g, 0.05 mmol) and X-Phos (0.049 g, 0.10 mmol) were added and the reaction mixture was heated in a microwave reactor at 120° C. for 40 minutes. The mixture was diluted with dichloromethane and was filtered though a plug of diatomaceous earth. The filter plug was washed with dichloromethane and methanol. The filtrate was concentrated and purified by preparative HPLC. The fractions containing product were pooled. NaHCO3 (aq) was added and the mixture was extracted with dichloromethane (×3). The combined organic phases were dried (MgSO4) and evaporated to give the title compound as a solid (16 mg, 7.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](Cl)=[O:6].[CH3:11][NH:12][CH2:13][CH2:14][C:15]#[N:16].C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C.O>[C:15]([CH2:14][CH2:13][N:12]([CH3:11])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1)#[N:16]
Reactant: CNCCC#N
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(CCC#N)C(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 g (0.0136 mol) of 2-chloroisonicotinoyl chloride was added dropwise to a solution comprising 1.2 g (0.01136 mol) of N-methyl-N-(2-cyanoethyl)amine, 1.9 ml (0.0136 mol) of triethylamine and 30 ml of acetonitrile under cooling at 5° to 10° C. The mixture was stirred at room temperature for 2 h and then poured into water. Ethyl acetate was added thereto to conduct extraction.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[Si:23]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)C1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Yield: 73.4 %

Procedure:
4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (7.34 g, 39.2 mmol) in N,N-dimethylformamide (200 mL) was stirred with imidazole (4.80 g, 70.6 mmol) and tert-butylchlorodimethylsilane (7.70 g, 51.0 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=25/1→4/1 (v/v)) to give the title compound as a colorless oil (8.68 g, yield 73%).
Reaction SMILES: N(C1CC1)=C=S.N.[CH:8]1([NH:11][C:12]([NH2:14])=[S:13])[CH2:10][CH2:9]1.Br[CH2:16][C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=O>C1COCC1.CO>[CH:8]1([NH:11][C:12]2[S:13][CH:16]=[C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1
Reactant: NC(=S)NC1CC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Agent: N
Agent: S=C=NC1CC1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2csc(NC3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Isothiocyanato-cyclopropane (4 g) was mixed with ammonia (37% in water, 8 mL) and methanol (32 mL) at 0° C. and then stirred for 16 hours at room temperature. The mixture was then cooled to 0° C., filtered, washed with a little water and dried. The Cyclopropyl-thiourea (2.06 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.06 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=261.0 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[CH3:12][C:13]1([OH:25])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C1C=CC=CC=1.CCOCC>[C:1]([O:25][C:13]1([CH3:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)(=[O:3])[CH3:2]
Reactant: CC1(O)CCCCC1C1CCCCC1
Reactant: CC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1(C)CCCCC1C1CCCCC1
Temperature: 40 °C

Procedure:
A mixture of 360 ml of acetyl chloride and 153 ml of acetic acid anhydride is added dropwise at 0° C., whilst stirring, to a solution of 576 g of crude 1-methyl-2-cyclohexylcyclohexanol in 750 ml of N,N-dimethylaniline. The mixture is then allowed to come to room temperature, after which it is heated to 40° C. for 36 hours. Thereafter, the reaction mixture is poured onto ice and diluted with 1 liter of ether, and the organic phase is separated off and concentrated ona Rotavapor apparatus. The residue is then taken up in 2 liters of ether and the solution is washed with three times 200 ml of cold 2-N HCl and then with saturated bicarbonate solution and water until neutral, and is dried with anhydrous MgSO4 and evaporated in vacuo. 646 g of crude 1-acetoxy-1-methyl-2-cyclohexylcyclohexane are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.Cl[C:19]([C:21]1[CH:22]=[C:23]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[N:24]2[C:28]=1[CH2:27][S:26][CH2:25]2)=[O:20].C>C(Cl)Cl.C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:19]([C:21]2[CH:22]=[C:23]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:24]3[C:28]=2[CH2:27][S:26][CH2:25]3)=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1cc(-c2cccnc2)n2c1CSC2
Reactant: COc1cccc(N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cccc(NC(=O)c2cc(-c3cccnc3)n3c2CSC3)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
A solution of 3-methoxyaniline (3.1 g) and of triethylamine (5.1 g) in methylene chloride (50 cc) is added over 15 minutes at a temperature of between 21° and 28° C. to a suspension of 7-chloroformyl-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (7.5 g) in methylene chloride (125 cc). The solution obtained is stirred at a temperature of about 20° C. for 16 hours. A product precipitates out. The crystals which have appeared are separated off by filtration, washed 3 times with methylene chloride (300 cc in total) and 3 times with distilled water (300 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. A crude product (5.1 g) melting at 220° C. is thus obtained. This product is dissolved in boiling 1-butanol (160 cc). The cloudy solution obtained is treated with decolourising charcoal (0.5 g) and filtered hot. The filtrate is cooled at a temperature of about 4° C. for 16 hours. The crystals which have appeared are separated off by filtration, washed twice with 1-butanol (30 cc in total) 3 times with ethanol (75 cc in total) and 3 times with diethyl ether (75 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. N-(3-Methoxyphenyl)-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.9 g) is thus obtained in the form of pale yellow crystals melting at 224° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2([C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH2:11][O:10]2)=[CH:3][CH:2]=1.[Na].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(O)CC>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:10])([CH2:11][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[C:12]([CH3:15])([CH3:16])[CH:13]=[CH2:14])=[CH:3][CH:2]=1
Reactant: C=CC(C)(C)C1(COc2ccc(-c3ccccc3)cc2)CO1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CCCO
Product: C=CC(C)(C)C(O)(COc1ccc(-c2ccccc2)cc1)Cn1ccnc1
Yield: 62.5 %

Procedure:
35.3 g (0.120 mol) of 2-(biphenyl-4-yloxymethyl)-2-(3,3-dimethylprop-1-en-3-yl)-oxirane, dissolved in 80 ml of n-propanol, were added to a boiling solution of 1 g (0.012 mol) of sodium propylate and 9 g (0.132 mol) of imidazole in 50 ml of n-propanol, in the course of 5 minutes. After the solution had been boiled under reflux for two days, the solvent was distilled off under reduced pressure, the residue was taken up in a mixture of 150 ml of ethyl acetate and 100 ml of dichloromethane, and the solution was washed with three times 50 ml of water. After the organic phase had been dried over anhydrous sodium sulphate, the solution was concentrated to dryness under reduced pressure. 10 ml of ethyl acetate were added to the solid residue, and the product was filtered off. 27.2 g (62.5% of theory) of 4-(biphenyl-4-yloxymethyl)-3,3-dimethyl-4-hydroxy-5-(imidazol-1-yl)pent-1-ene were obtained in the form of colorless crystals of melting point 151° to 153° C. in this manner.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7](OS(C2C=CC=CC=2S(N(C)C2CCN(C)CC2)(=O)=O)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15](=[NH:17])[NH2:16].CC1C=CC([O:64][S:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[S:74]([N:77]([CH3:85])[CH:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)(=[O:76])=[O:75])(=[O:67])=[O:66])=C(C=1)OCCCOC1C=CC=C2C(NC(=O)C=12)=O.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:64][S:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[S:74]([N:77]([CH3:85])[CH:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)(=[O:75])=[O:76])(=[O:67])=[O:66])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c(OCCCONC(=N)N)c1
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c(OCCCOc2cccc3c2C(=O)NC3=O)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c1
Yield: 76 %

Procedure:
N-{3-[5-Methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl) phenylsulfonyloxy]phenoxy]propoxy}guanidine dihydrochloride: The title compound was prepared in 76% yield from N-{3-[5-methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl) aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 8.25 (d, J=7.9 Hz, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.02 (t, J=7.6 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.37 (br s, 4H), 6.75 (s, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 4.07 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.22 (m, 2H), 3.17 (s, 3H), 2.79 (s, 3H), 2.72 (t, J=12.0 Hz, 2H), 2.22 (s, 3H), 1.99 (pentet, J=6.3 Hz, 4H), 1.60 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C24H35N5O7S2: 570.2 (M+H), 592.2 (M+Na). Found: 570.1, 592.1.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]2[C:12]([O:14][C:15](=[O:16])[C:10]=12)=O.Cl.[NH2:21][CH:22]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:23]1=[O:24]>CN(C=O)C>[O:24]=[C:23]1[CH:22]([N:21]2[C:15](=[O:16])[C:10]3[C:11](=[CH:17][CH:18]=[CH:19][C:9]=3[OH:8])[C:12]2=[O:14])[CH2:28][CH2:27][C:26](=[O:29])[NH:25]1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2c(O)cccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Triethylamine (2.70 mL, 19.4 mmol) was added to a mixture of 3-hydroxyphthalic anhydride (3.00 g, 18.3 mmol) and rac-α-aminoglutarimide hydrochloride (3.01 g, 18.3 mmol) in DMF (60 mL). The reaction mixture was heated to 90° C. overnight, then cooled to room temperature and the solvent was evaporated under vacuum. The residue was stirred in CH2Cl2 (100 mL) for 30 min and the solvent was removed under vacuum. The residue was stirred in water (120 mL) for 2 h and the resulting solid was filtered, washed with water (50 mL) and dried. 1,4-Dioxane (200 mL) was added, and the resulting suspension was stirred for 16 h and filtered; the insoluble material was reserved. The filtrate was treated with decolorizing carbon (2 g) and heated to reflux for 1 h. After cooling to 50° C., the reaction mixture was filtered through Celite and the filter was washed with additional 1,4-dioxane (50 mL). The filtrate was combined with the insoluble precipitate and evaporated to dryness. The resulting solid was triturated with ethyl acetate (100 mL), filtered and dried to give 2-(2,6-dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione, 4.18 g, in 56% yield; 1H NMR (DMSO-d6) δ 1.99-2.06 (m, 1H), 2.45-2.61 (m, 2H), 2.82-2.96 (m, 1H), 5.08 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 7.23-7.33 (m, 2H), 7.66 (dd, J=8.2 Hz, J=7.2 Hz, 1H), 11.10 (s, 1H), 11.19 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]1[S:54][C:55]2[CH:61]=[C:60]([O:62][S:63]([C:66]3[CH:71]=[CH:70][C:69]([NH:72][CH2:73][CH2:74][N:75]([CH:79]([CH3:81])[CH3:80])[CH:76]([CH3:78])[CH3:77])=[CH:68][CH:67]=3)(=[O:65])=[O:64])[CH:59]=[CH:58][C:56]=2[N:57]=1>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:52][C:53]1[S:54][C:55]2[CH:61]=[C:60]([O:62][S:63]([C:66]3[CH:71]=[CH:70][C:69]([NH:72][CH2:73][CH2:74][N:75]([CH:79]([CH3:81])[CH3:80])[CH:76]([CH3:77])[CH3:78])=[CH:68][CH:67]=3)(=[O:65])=[O:64])[CH:59]=[CH:58][C:56]=2[N:57]=1)=[O:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1)C(C)C
Reactant: CC(C)(C)OC(=O)NCCCCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)CCCCCCCNC(=O)OC(C)(C)C)sc3c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
175 mg of 8-tert-butoxycarbonylaminooctanoic acid, 256 mg of HBTU and 235 μl of DIEA are added to a solution of 4-(2-diisopropylaminoethylamino)-benzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 34) (100 mg, 0.225 mmol) in 5 ml of dimethylformamide. The solution obtained is stirred for 20 hours at room temperature. After addition of 50 ml of water, the reaction mixture is extracted with 3 times 25 ml of ethyl acetate. The extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 338 mg of crude oil. This oil is purified by elution in a 95/5 dichloromethane/methanol mixture at a flow rate of 10 ml/minute, on 10 g of silica, to give 153 mg of 4-(2-diisopropylaminoethylamino)benzenesulfonic acid 2-(8-tert-butoxycarbonylaminooctanoylamino)benzothiazol-6-yl ester.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]5[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]5)=[O:29])=[CH:26][C:25]=4[O:40][CH3:41])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC1(CC1)C(=O)N2C
Yield: 57.1 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 100 mg, 0.31 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 83 mg, 0.31 mmol) and p-toluenesulphonic acid monohydrate (149 mg, 0.78 mmol) were heated at 140° C. in 4-methyl-2-pentanol (4 mL) for 2 hours. The reaction mixture was loaded onto an SCX-3 column was pre-wet with methanol and the column washed with methanol and eluted with 2% 7N ammonia/methanol. The ammoniacal fraction was evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (97 mg, 57%)
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[CH2:7]([NH:14]N)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)CCCC>[NH2:5][C:4]1[N:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:1]=[C:2]([CH3:6])[CH:3]=1
Reactant: C/C(N)=C/C#N
Reactant: NNCc1ccccc1
Solvent: CCCCCO
Product: Cc1cc(N)n(Cc2ccccc2)n1
Yield: 45.4 %

Procedure:
To a solution of 16.4 g (0.2 mol) of 3-aminocrotononitrile in 100 cm3 of n-pentanol were added 26.9 g (0.22 mol) of benzylhydrazine and the mixture was then heated at reflux for 12 hours. The n-pentanol was subsequently distilled off under reduced pressure and a thick oil was obtained, which was purified by chromatography on silica gel. A pale yellow solid was obtained, which was crystallized from isopropyl ether and was then filtered on a sinter funnel. After drying under vacuum at 40° C., 17 g of the expected product were obtained in the form of a pale yellow solid, the melting point of which was from 76 to 78° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:9][C:3]1[C:2]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
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: O
Solvent: COCCOC
Product: Cc1cnc(N)c(-c2ccc(O)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.716 g) was added to a suspension of 3-bromo-5-methylpyridin-2-amine (3.86 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g) and sodium carbonate (2.19 g) in DME (150 mL) and water (30 mL) and the mixture was stirred at 80° C. under nitrogen for 5 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1.99 g) as a pale yellow solid.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[N:44]1([C:49](Cl)=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:49]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)=[O:50])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)N1CCCC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (45 mg, 0.087 mmol) in DCM (870 μL) at 0° C. was treated with triethylamine (36.4 μL, 0.261 mmol), followed by pyrrolidine-1-carbonyl chloride (19.2 μL, 0.174 mmol). The reaction mixture was allowed to stir for 30 min, gradually warming to room temperature. The reaction mixture was concentrated under reduced pressure and purified directly by HPLC Method B, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column was used, using a 50% to 80% ACN gradient to give the title compound, as a TFA salt, as a pale yellow solid (10.6 mg, 19.8%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.33 (d, J=6.3 Hz, 6H), 1.89 (m, 4H), 1.97 (m, 2H), 2.14 (m, 2H), 2.81 (t, J=5.8 Hz, 2H), 3.13 (m, 2H), 3.46 (m, 6H), 3.61 (t, J=5.8 Hz, 2H), 4.12 (septet, J=6.4 Hz, 1H), 4.38 (s, 2H), 4.51 (tt, J=7.2, 3.6 Hz, 1H), 6.88 (m, 1H), 6.99 (ddd, J=11.4, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 501.6.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][C:22]([F:25])([F:24])[O:21][C:20]([F:27])([F:26])[C:19]=2[CH:28]=1>C1(C)C=CC=CC=1>[F:25][C:22]1([F:24])[O:21][C:20]([F:26])([F:27])[C:19]2[CH:28]=[C:15]([NH:14][C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=3[F:13])[CH:16]=[CH:17][C:18]=2[O:23]1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 5.5 g (0.03 mol) of 2,6-difluorobenzoyl isocyanate in 20 ml of toluene was added dropwise, at 60° C, to 6.7 g (0.03 mol) of 6-amino-2,2,4,4-tetrafluorobenz-1,3-dioxin in 100 ml of toluene. The batch was stirred for 1 hour at 60° C. After it had cooled, the product which had precipitated was filtered off, washed first with toluene and then with petroleum ether and then dried. 8 g (65.5% of theory) of analytically pure 3-(2,2,4,4-tetrafluoro-benz-1,3-dioxin-6-yl)-1-(2,6-difluorobenzoyl)-urea of melting point 231° C were obtained.