Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:18](=[O:19])[CH:17]3[CH2:20][CH2:21][CH2:22][C:16]3=[N:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.CCCCCC>[C:1]1([CH2:11][N:12]2[C:18](=[O:19])[C@H:17]3[CH2:20][CH2:21][CH2:22][C@H:16]3[NH:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C2CCCC2=Nc2ccccc2N1Cc1cccc2ccccc12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1cccc2ccccc12
Yield: 67 %

Procedure:
Using 9-(1-naphthylmethyl)-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the titled compound was synthesized in substantially the same manner as in Working Example 24 in a yield of 67%, m.p. 126°-128° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=1)[CH2:20][CH:21]([C:23]([OH:25])=[O:24])[NH2:22]>CS(C)=O>[C:23]([CH:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[CH:26]=[CH:27][CH:28]=[C:17]([F:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: NC(Cc1cccc(F)c1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1cccc(F)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloro-quinoline-3-carboxylic acid is reacted with 3-fluoro-DL-phenylalanine in DMSO to provide the title compound in high yield.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C[Mg]Br>C1COCC1>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)c1ccccn1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1ccccn1
Temperature: 25 °C

Procedure:
A stirred solution of ethyl 2-oxo-(pyridin-2-yl)acetate (1.0 g, 5.6 mmol) in THF (15 mL) was cooled to −78° C. under an atmosphere of nitrogen. To this solution was added methyl magnesium bromide in THF (6.2 mL of a 1.0 M solution, 6.2 mmol) dropwise over 5 min. The cooling bath was removed and the stirred mixture was allowed to warm to ambient temperature over 2 h. Water (30 mL) was added and the mixture was extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:2 EtOAc:hexanes as eluant. Product-containing fractions were combined and the solvents were removed under reduced pressure to give ethyl 2-hydroxy-2-(2-pyridyl)acetate as a colorless liquid (0.90 g, 83%; HPLC RT=1.46 min, method A; TLC Rf=0.3 (1:2 EtOAc:hex); LCMS m/z=196; 1H NMR (400 MHz, CDCl3): δ 8.55 (dd, J=0.9, 4.8 Hz, 1H), 7.74 (dt, Jd=1.1 Hz, Jt=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.26 (dd, J=4.5, 8.0 Hz, 1H), 5.45 (s, 1H), 4.19 (q, J=7.0 Hz, 2H), 1.82 (s, 3H), 1.23 (t, J=7.0 Hz, 3H)).
Reaction SMILES: C([Li])CCC.C1C[O:9][CH2:8]C1.[F:11][C:12]1[C:17]([O:18][CH2:19][O:20][CH3:21])=[CH:16][CH:15]=[CH:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.[Cl-].[NH4+]>CN(C=O)C>[F:11][C:12]1[C:17]([O:18][CH2:19][O:20][CH3:21])=[C:16]([CH:8]=[O:9])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1
Reactant: COCOc1cccc(-c2ccc(F)cc2)c1F
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCOc1c(C=O)ccc(-c2ccc(F)cc2)c1F
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6 M hexane solution, 52.2 mL) was added at −78 C to an anhydrous THF (200 mL) solution of 2,4′-difluoro-3-(methoxymethoxy)biphenyl (19.0 g) in an argon atmosphere, and then, the mixture was stirred at −78 C for 1 hour. DMF (12.9 mL) was added thereto, and then, the mixture was stirred for 3 hours in an argon atmosphere while heated from −78 C to 0 C. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was separated, then washed with saturated saline, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was solidified with hexane to obtain the title compound (16.4 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:27]=[C:28]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)[CH:29]=[CH:30][CH:31]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:50]1([CH2:56][CH2:57][OH:58])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:50]1([CH2:56][CH2:57][O:58][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:27]=[C:28]([N:32]6[S:36](=[O:37])(=[O:38])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:34](=[O:47])[CH2:33]6)[CH:29]=[CH:30][CH:31]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O
Reactant: OCCC1CCCCC1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure L using 2-cyclohexyl ethanol (35 μL, 0.25 mmol) to give 5-{3-[2-{-4-[6-(2-cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([O:12][CH2:13][C:14]4[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=4[F:21])=[CH:10][CH:9]=[CH:8][N:7]3[C:22]=2[C:23]([O:25]CC)=[O:24])[CH2:3][CH2:2]1.[OH-].[Li+]>CO.O1CCCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([O:12][CH2:13][C:14]4[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=4[F:20])=[CH:10][CH:9]=[CH:8][N:7]3[C:22]=2[C:23]([OH:25])=[O:24])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(C2CC2)nc2c(OCc3c(F)cccc3F)cccn12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(C2CC2)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
410 mg of ethyl 2-cyclopropyl-8-[(2,6-difluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate (Example 27A, 1.1 mmol, 1 equivalent) were initially charged in 15 ml of methanol/tetrahydrofuran (1:1), and 5.5 ml of a 1 N aqueous lithium hydroxide solution (5.5 mmol, 5 equivalents) were added. The reaction mixture was stirred at RT overnight, another 5.5 ml of 1 N aqueous lithium hydroxide solution were added, and the mixture was stirred at RT for another night. The mixture was concentrated and the residue was taken up in water and acidified with 1 N aqueous hydrochloric acid. The precipitated product was filtered off and dried under high vacuum. This gave 293 mg (77% of theory) of the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[CH3:26])[C:20]([OH:22])=O)=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.[CH3:27][C:28]1[N:29]=[CH:30][N:31]([C:33]2[CH:34]=[C:35]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[NH2:36])[CH:32]=1>>[CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([C:20](=[O:22])[NH:36][C:35]5[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=[C:33]([N:31]6[CH:32]=[C:28]([CH3:27])[N:29]=[CH:30]6)[CH:34]=5)[CH:23]=[CH:24][C:25]=4[CH3:26])=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(NC(=O)c4csc5c(NC6CC6)ncnc45)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 3 of Example 21 and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[N:17]2)[CH:11]=1.NC1C=NC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:57][C:58]1[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:59]=1[O:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[F:57][C:58]1[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:59]=1[O:60][CH:61]1[CH2:62][CH2:63][N:64]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[N:17][N:16]([C:12]3[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=3)[CH:20]=2)=[O:22])[CH2:65][CH2:66]1
Reactant: Fc1ccc(F)c(OC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cn(-c2cccnc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)CC1)c1cn(-c2cccnc2)nn1
Reaction time: 0.03 h
Yield: 46.5 %

Procedure:
DIPEA (135.9 mg, 1.05 mmol) was added to a stirred solution of [(1-pyridin-3-yl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine, and subsequently, application of Step 3 of the General Scheme) (65 mg, 0.26 mmol) in DMF (2 mL) followed by HOBt (39 mg, 0.29 mmol) and EDCI (101 mg, 0.52 mmol). After 2 minutes of stirring, 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (65.6 mg, 0.26 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the resultant was extracted with DCM. The organic layer was collected and dried over sodium sulfate and concentrated under reduced pressure The residue obtained was purified by stirring in mixture of 30% EtOAc in hexane (10 mL), H2O (0.5 mL) and MeOH (0.5 mL) for 30 minutes. Filtered the mixture to afford 54 mg (46.5% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 443.16, 92.48%. 1H NMR (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 9.2 (d, 1H), 8.75 (m, 1H), 8.5 (t, 1H), 8.4 (m, 1H), 7.7 (q, 1H), 7.32-7.2 (m, 2H), 6.7-6.4 (m, 1H), 4.8-4.7 (m, 1H), 4.25 (d, 2H), 4.0-3.8 (m, 1H), 3.8-3.7 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.1-1.9 (m, 2H), 1.8-1.5 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(NCc3ccc(Cl)cc3)cc2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a mixture of (RS)-2-(4-amino-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, CAS 1002726-96-6), 4-chlorobenzaldehyde (33.3 mg) and AcOH (123 μl) in THF (2 ml) was added sodium triacetoxyborohydride (68.5 mg). The reaction mixture was then capped and the mixture was shaken at 60° C. for 3 h. The crude reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 65% EtOAc in hexanes) to afford (RS)-2-[4-(4-chloro-benzylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (68 mg, 78%) as a colourless oil. MS (ISP): 405.4 ([{37Cl}M+H]+), 403.4 ([{35Cl}M+H]+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=1)(=O)=O.[Cl-].[Li+].[Br-].[CH3:22][C:23]1[N:28]=[C:27]([Zn+])[CH:26]=[CH:25][CH:24]=1>O1CCCC1.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>[CH2:13]([C:9]1[N:8]=[C:7]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:22])[N:28]=2)[CH:12]=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Cc1cccc([Zn+])n1
Reactant: CCCCc1cccc(OS(=O)(=O)C(F)(F)F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCc1cccc(-c2cccc(C)n2)n1
Reaction time: 1 h

Procedure:
To a flask were added 1.2 g 6-butylpyridin-2-yl trifluoromethanesulfonate, 0.36 g lithium chloride and 10 ml dry tetrahydrofuran. Addition of 12 ml of a 0.5M solution of 6-methyl-2-pyridylzinc bromide in tetrahydrofuran was followed by addition of 242 mg of tetrakis(triphenylphosphine)palladium. The reaction was heated to reflux under nitrogen for 16 hours. The reaction was cooled to 22 C and quenched by adding a solution of 6 g of ethylene diamine tetraacetic acid in 40 ml water pH adjusted to 8 with aqueous sodium bicarbonate. 50 ml Hexane and 20 ml ethyl acetate were added and the mixture was stirred for one hour before the aqueous layer was removed and the organic layer was dried over sodium sulfate. After filtration and solvent removal, the product was purified by silica gel chromatography using 5% ethyl acetate in hexane to give 0.7 g clear colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:14])[CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:17][C:18]1[C:21](=[O:22])[C:20](=O)[C:19]=1[NH:24][C:25]1[C:26]([OH:36])=[C:27]([CH:33]=[CH:34][CH:35]=1)[C:28]([N:30]([CH3:32])[CH3:31])=[O:29])C>CO>[OH:36][C:26]1[C:25]([NH:24][C:19]2[C:18](=[O:17])[C:21](=[O:22])[C:20]=2[NH:14][CH:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:35][CH:34]=[CH:33][C:27]=1[C:28]([N:30]([CH3:32])[CH3:31])=[O:29]
Reactant: Cc1ccc(C(N)C2CCOCC2)o1
Reactant: CCOc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N(C)C)c3O)c(=O)c2=O)C2CCOCC2)o1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94.1 %

Procedure:
644 mg (3.3 mmol, 2 eq) of C-(5-methylfuran-2-yl)-C-(tetrahydropyran-4-yl)methylamine were added to 500 mg (1.64 mmol, 1 eq) of 3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide dissolved under hot conditions in 50 ml of methanol. The reaction medium was stirred at ambient temperature for 21 hours. The methanol was evaporated off and the residue (green oil) was chromatographed on silica gel (column Analogix SF15-40 g, Spot II) eluted with dichloromethane/methanol (gradient). 700 mg of 2-hydroxy-N,N-dimethyl-3-(2-{[(5-methylfuran-2-yl)-(tetrahydropyran-4-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzamide were obtained. (M.p.=137-140° C.). Yield=94%. LC/MS: 97.1% [453]
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](Br)=[CH:4][N:3]=1.CCO[C:13]([S-:15])=[S:14].[K+].O.OS(O)(=O)=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:15][C:13](=[S:14])[NH:8][C:6]=2[N:7]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ncc(Br)c(N)n1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc2sc(=S)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 2,4-diamino-5-bromo-pyrimidine (9.5 g, 50 mmol, 1.0 eq) and potassium ethyl xanthogenate (16 g, 100 mmol. 2 eq) in DMF (300 ml) was heated up to reflux for 10 hours under N2. The reaction solution was cooled down to room temperature and water (600 ml) was added. The pH of the solution was then adjusted to about 5 using H2SO4 (2 ml) and the resulting suspension was stirred at 50-60° C. for 30 min., cooled to about 30° C., filtered and washed with water. The product was dried under vacuum at 50-60° C. to give 8.2 g (89%) of 5-amino-3H-thiazolo[4,5-d]pyrimidin-2-thione as a yellow solid. 1H NMR (400 MHz, d6-DMSO). δ 6.91 (s, 2H, ex. D2O), 8.34 (s, 1H), 12.3 (br, 1H, ex. D2O); MS (+)-ES [M+H]+ m/z 185.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14](C(OC)=O)CC3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.ClC1C(CNC([C@H]2CC[C@H](C(OC)=O)CC2)=O)=NC=CN=1.C1(C(O)=O)CCC1.C1(C(O)=O)CCCCC1>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][CH2:14]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Agent: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Agent: O=C(O)C1CCC1
Solvent: O=C(O)C1CCCCC1
Product: Clc1nccn2c(C3CCC3)ncc12

Procedure:
This compound was prepared using procedures analogous to that described for trans-methyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate and its precursor trans-methyl 4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)cyclohexanecarboxylate, using cyclobutanecarboxylic acid in place of 4<methoxycarbonyl)cyclohexanecarboxylic acid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccccc1
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Yield: 71 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and phenylhydrazine according to the method described for Example 1 in 71% yield. MS: M=345.1 (M+H)+
Reaction SMILES: [CH3:1][S@:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[NH:4])=[O:3].[CH3:11][Si:12](N(CC)CC)([CH3:14])[CH3:13]>C(#N)C>[CH3:11][Si:12]([CH3:14])([CH3:13])[N:4]=[S@@:2]([CH3:1])(=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCN(CC)[Si](C)(C)C
Reactant: C[S@](=N)(=O)c1ccccc1
Solvent: CC#N
Product: C[Si](C)(C)N=[S@@](C)(=O)c1ccccc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a stirred pre-warmed solution of (S)-(+)-S-methyl-S-phenylsulphoximine (3 g, 18.7 mmol) in acetonitrile (2 mL) at 65° C. was added (trimethylsilyl)diethylamine (4.12 g, 21.1 mmol) dropwise via a syringe. The reaction was maintained at 65° C. and stirred for 3 hours. Additional amount of (trimethylsilyl)diethylamine (2 mL, 10.2 mmol) was added and the reaction mixture was stirred at 65° C. overnight. The reaction was then concentrated under reduced pressure and dried under vacuum to give the title compound. This material was used directly in next step of the synthesis without further purification.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([O:15]C)=[O:14])=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:6]1(=[O:24])=[O:23])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-].Cl>O1CCOCC1.O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:6]1(=[O:24])=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C)(C)N1C(=O)C(NCC(=O)O)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
Methyl [(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]acetate (1.28 g, 3.64 mmol) was dispersed in a mixture of dioxane (20 mL), MeOH (20 mL) and water (20 mL). Aqueous LiOH (1M, 0.218 g, 9.10 mmol) was added and the reaction mixture was stirred at rt for 2 h. Aqueous HCl was carefully added to the reaction mixture to give the pH˜1 and the resulting mixture was extracted with DCM. The organic phases were combined, dried over Na2SO4, filtered, evaporated and the crude residue was purified by preparative HPLC giving the title compound (0.51 g, 41%). 1H-NMR (CD3OD, 500 MHz): δ 7.52-7.48 (m, 2H), 7.46-7.42 (m, 3H), 5.41 (brs, 8H) 1.95 (s, 2H), 1.71 (s, 9H); 13C-NMR (CD3OD, 125 MHz): δ 178.4, 174.8, 160.8, 136.5, 132.8, 130.4, 129.5, 126.6, 107.4, 62.1, 48.3, 27.9, 22.9.
Reaction SMILES: Br/[CH:2]=[C:3]1\[C:4]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:5]=2[CH2:6][CH2:7][C:8]2[C:13]\1=[CH:12][CH:11]=[CH:10][N:9]=2.CC1(C)C(C)(C)OB([C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[NH:33][C:29]=3[CH:28]=2)O1>>[F:18][C:15]1[CH:16]=[CH:17][C:4]2/[C:3](=[CH:2]\[C:27]3[CH:36]=[CH:35][C:30]4[NH:31][C:32](=[O:34])[NH:33][C:29]=4[CH:28]=3)/[C:13]3[C:8]([CH2:7][CH2:6][C:5]=2[CH:14]=1)=[N:9][CH:10]=[CH:11][CH:12]=3
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Fc1ccc2c(c1)CCc1ncccc1/C2=C/Br
Product: O=c1[nH]c2ccc(/C=C3\c4ccc(F)cc4CCc4ncccc43)cc2[nH]1
Yield: 59.4 %

Procedure:
Following procedures essentially as desctribed in Example 219, beginning with (E)-5-bromomethylene-8-fluoro-10,11-dihydro-benzo[4,5]cyclohepta[1,2-b]pyridine (100 mg, 0.33 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (111 mg, 0.43 mmol). After work-up, purify the crude product by flash chromatography (100% ethyl acetate to 10% ethanol/ethyl acetate) to provide 70 mg (60%) of purified product. LCMS (APCI-pos): 358.0 (M+H). LCMS (APCI-neg): 356.0 (M−H). Purity by LCMS (UV Area percent): 99%. 1HNMR (d6-DMSO, 400 MHz): δ10.56 (s, 1H), 10/46 (s, 1H), 8.38 (dd, 1H), 7.88 (dd, 1H), 7.28 (dd, 1H), 7.23 (dd, 1H), 6.96-6.90 (m, 2H), 6.89 (s, 1H), 6.73 (d, 1H), 6.68 (d, 1H), 6.52 (s, 1H), 3.5-3.3 (m, 2H), 3.1-2.9 (m, 2H).
Reaction SMILES: [BH4-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[N:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:16]([CH3:18])[N:17]=2)[CH2:8][CH2:7]1>CO>[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[NH:13][N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]([CH3:18])[N:17]=2)[CH2:8][CH2:7]1
Reactant: Cc1nc(N2CCN(CCO)CC2)nnc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1N=C(N2CCN(CCO)CC2)NN=C1c1ccccc1
Yield: 62.9 %

Procedure:
Sodium borohydride (2.72 g) was added portionwise to a stirred solution of 3-[4-(2-hydroxyethyl)-1-piperazinyl]-5-methyl-6-phenyl-1,2,4-triazine (3.6 g) in methanol (15 ml) at room temperature. The reaction mixture was filtered by suction and the filtrate was evaporated. The resultant residue was extracted with ethyl acetate after addition of water, and the extract was washed with brine, dried over sodium sulfate and concentrated to a small volume. The resultant precipitates were collected by filtration, washed with diisopropyl ether and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 3-[4-(2-hydroxyethyl)-1-piperazinyl]-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (2.28 g), mp 103°~105° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(C(F)F)c(C(=O)O)c1Cl
Product: Cn1nc(C(F)F)c(C(=O)Cl)c1Cl

Procedure:
3.2 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and 44.3 mL of thionyl chloride were heated under reflux for 5 h. After cooling, the reaction mixture was concentrated under reduced pressure, giving 3.5 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride as a yellow oil.