Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23][CH2:22]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1)[CH2:23][CH2:22]2
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(F)ccc3C2)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 100 °C
Yield: 73.5 %

Procedure:
In a tube, a mixture of 1d (0.65 g, 2.15 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (0.348 g, 2.6 mmol) in toluene (15 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.052 g, 0.055 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.08 g, 0.2 mmol) and potassium tert-butoxide (0.437 g, 3.9 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title compound (0.584 g, 1.58 mmol, 73%). 1H NMR (CDCl3, 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J=6.2 Hz, 2H), 3.82 (t, J=6.2 Hz, 2H), 4.62 (s, 2H), 6.38 (s, 1H), 6.50 (bs, 1H), 6.85-6.92 (m, 2H), 7.09-7.16 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([O:48]CC5C=CC=CC=5)=[CH:44][CH:43]=4)[CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[H][H]>[Pd].C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:41][C:42]4[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=4)[CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccc(OCc3ccccc3)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccc(O)cc2)c1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 4C (0.05 g) and 5% palladium on carbon (0.1 g) in ethanol (5 mL) was treated with a balloon of hydrogen. The reaction mixture was stirred overnight. The solid was removed by filtration, and filtrate was concentrated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:19][C@:20]([CH3:26])([CH:23]([CH3:25])[CH3:24])[CH2:21][OH:22]>>[OH:22][CH2:21][C@@:20]([NH:19][C:8]([C:5]1[CH:4]=[C:3]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)[C@@](C)(N)CO
Reactant: O=C(O)c1cc(Cc2ccc(F)cc2)c(Cl)cn1
Product: CC(C)[C@](C)(CO)NC(=O)c1cc(Cc2ccc(F)cc2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-(4-fluorobenzyl)-pyridine-2-carboxylic acid and (2R)-2-amino-2,3-dimethyl-1-butanol (CAN 155158-75-1) as starting materials and isolated (29 mg, 25%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 365.1428 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[Br:7][C:6]1[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1onc(N)c1Br
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1onc(NC(=O)OCC(Cl)(Cl)Cl)c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-amino-4-bromo-5-methylisoxazole (2.58 g, 14.6 mmol) and DMAP (893 mg, 7.3 mmol) in 60 mL dichloromethane at −78° C. was added pyridine (6 ml, 74.1 mmol) followed by 2,2,2-trichloroethyl chloroformate (8 ml, 58 mmol). The reaction was allowed to warm to room temperature while stirring over ca. 4 hours. Ice water was added, the aqueous phase neutralized with saturated aq. NaHCO3, and the product extracted with ether (3×), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (20% ethyl acetate/hexane) to afford 2,2,2-trichloroethyl 4-bromo-5-methylisoxazol-3-ylcarbamate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:24][CH:25]1[CH2:27][CH2:26]1)[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:24][CH:25]1[CH2:27][CH2:26]1)(=[O:22])[NH2:23]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=372.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:5]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=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>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:3]=[C:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Yield: 44.5 %

Procedure:
A solution of ethyl 4-chloro-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-5-carboxylate (30 mg, 0.07 mmol) and phenyl boronic acid (14 mg, 0.11 mmol) in toluene (3 mL) was degassed with argon for 15 minutes. To this solution was added Pd(PPh3)4 (9 mg, 0.007 mmol), Na2CO3 (23 mg, 0.22 mmol) and the reaction was heated to reflux for 3 days. The reaction was diluted with EtOAc (20 mL) and extracted with saturated NH4Cl solution (2×20 mL), brine (20 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude reaction product was purified by flash chromatography (silica gel, 20% EtOAc/hexane) to give ethyl 4-(2,4-dichlorophenyl)-2,6-diphenylpyrimidine-5-carboxylate (14 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=O)[NH:11][N:10]=1.P(Br)(Br)([Br:25])=O>C(#N)C>[Br:25][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:9]([CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:22])=[N:10][N:11]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[nH]c(=O)c2c1
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Br)c2c1
Yield: 82.5 %

Procedure:
A suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-2H-phthalazin-1-one (10 g, 25.5 mmoles), prepared as described in example 38, in acetonitrile (300 ml), was added with POBr3 (22 g, 76.5 mmoles) and the mixture was refluxed. After 1 night under reflux and another to stand, the solution was concentrated, taken up in water, cooled in ice and alkalinised with concentrated NaOH. There was extracted three times with CH2Cl2 and the organic phases were discoloured with charcoal, anhydrified and concentrated. The crude was purified by flash chromatography (eluent: petrolatum/ethyl acetate 8:2, then 6:4) to give 8.4 g of the title compound (yield: 82%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:5]([Cl:16])=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:3]=1.Cl.[F:25][C:26]1[CH:27]=[N:28][C:29]([C@@H:32]([NH2:34])[CH3:33])=[N:30][CH:31]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:5]1[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[N:7][C:2]([NH:34][C@H:32]([C:29]2[N:30]=[CH:31][C:26]([F:25])=[CH:27][N:28]=2)[CH3:33])=[N:3][C:4]=1[NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1
Reactant: Cc1cc(Nc2nc(Cl)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Temperature: 160 °C
Yield: 89.4 %

Procedure:
A microwave reaction vessel was charged with N-{2,5-dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N′,N′-trimethylsulfamide (Method 24, 83.9 mg, 0.221 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 78.4 mg, 0.443 mmol), and DIPEA (0.120 ml, 0.682 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexane) to afford the title compound as a white solid (95.8 mg, 89.6%). LC-MS, 485 (M+1). 1H-NMR (DMSO-d6, 400 MHz, 80° C.) δ 11.48-12.40 (br, 1H), 8.77 (s, 1H), 7.85-8.66 (br, 1H), 6.98-7.61 (br, 1H), 6.23 (s, 1H), 5.14-5.11 (m, 1H), 2.93 (s, 3H), 2.83 (s, 6H), 2.21 (s, 3H), 1.53 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]([CH2:14]O)[C:11]([CH3:16])=[N:10]1.[OH-].[Na+].[BrH:19]>O>[Br:19][CH2:14][C:12]1[C:11]([CH3:16])=[N:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:13]=1
Reactant: Cc1nn(-c2ccc(F)cc2F)nc1CO
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2F)nc1CBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(2,4-Difluorophenyl)-5-methyl-2H-1,2,3-triazole-4-methanol (i.e. the product of Step B, 0.70 g, 3.1 mmol) was suspended in 48% hydrobromic acid in water (16 mL). The mixture was heated to reflux with stirring for 2 h. The reaction mixture was diluted with water, cooled to 0° C. and basified with 50% aqueous sodium hydroxide solution. The reaction mixture was extracted with ethyl acetate, dried (MgSO4) and concentrated under reduced pressure to obtain the title compound (0.75 g) as a pale yellow oil. The title compound was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:21]2[S:25][C:24]([NH:26][C:27](=O)[O:28]C3C=CC=CC=3)=[N:23][CH:22]=2)[N:9]=1.CN.[CH2:38]([N:40](CC)CC)C>CN1C(=O)CCC1>[CH3:38][NH:40][C:27](=[O:28])[NH:26][C:24]1[S:25][C:21]([C:10]2[N:9]=[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=2)=[CH:22][N:23]=1
Reactant: CCN(CC)CC
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(NC(=O)Oc3ccccc3)s2)n1
Agent: CN
Solvent: CN1CCCC1=O
Product: CNC(=O)Nc1ncc(-c2nc(N3CCOC[C@@H]3C)cc(C(C)(C)S(C)(=O)=O)n2)s1

Procedure:
A solution of phenyl N-[5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-yl]-1,3-thiazol-2-yl]carbamate (200 mg, 0.39 mmol), methyl amine (1.5 mmol) and triethylamine (0.163 mL, 1.16 mmol) in NMP (3 mL) was heated at 70° C. for 2 hours. The mixture was chromatographed on silica, eluting with 0-5% methanol in ethyl acetate to give the desired material.
Reaction SMILES: CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.[Si]([O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][C@@H:45]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([S:61]([NH:64][C:65](=[O:99])[C:66]3[CH:71]=[CH:70][C:69]([N:72]4[CH2:77][CH2:76][CH:75]([C@H:78]([C:86]5[CH:91]=[CH:90][CH:89]=[CH:88][C:87]=5[C:92]5[CH:97]=[CH:96][C:95]([Cl:98])=[CH:94][CH:93]=5)[NH:79][S@:80]([C:82]([CH3:85])([CH3:84])[CH3:83])=[O:81])[CH2:74][CH2:73]4)=[CH:68][CH:67]=3)(=[O:63])=[O:62])=[CH:57][C:56]=2[S:100]([C:103]([F:106])([F:105])[F:104])(=[O:102])=[O:101])[CH2:46][S:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:39][CH2:38]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[Cl:98][C:95]1[CH:94]=[CH:93][C:92]([C:87]2[CH:88]=[CH:89][CH:90]=[CH:91][C:86]=2[C@H:78]([NH:79][S@:80]([C:82]([CH3:85])([CH3:84])[CH3:83])=[O:81])[CH:75]2[CH2:74][CH2:73][N:72]([C:69]3[CH:68]=[CH:67][C:66]([C:65]([NH:64][S:61]([C:58]4[CH:59]=[CH:60][C:55]([NH:54][C@H:45]([CH2:44][CH2:43][N:40]5[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][OH:34])[CH2:42][CH2:41]5)[CH2:46][S:47][C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)=[C:56]([S:100]([C:103]([F:106])([F:105])[F:104])(=[O:101])=[O:102])[CH:57]=4)(=[O:63])=[O:62])=[O:99])=[CH:71][CH:70]=3)[CH2:77][CH2:76]2)=[CH:97][CH:96]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCN(CCO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCN(CCO)CC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Reaction time: 1 h
Yield: 128.1 %

Procedure:
A solution of TASF (0.58 ml. 0.58 mmol, 1.0M in DMF) was added to a solution of N-(4-((R)-4-(4-(2-(tert-butyldiphenylsilyloxy)ethyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethyl sulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzamide (EXAMPLE 13, STEP 2, 0.39 g, 0.29 mmol) in DMF (2.3 ml) and the reaction mixture was stirred at r.t for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with DCM and washed with H2O. The organic layer was dried (Na2SO4), concentrated under reduced pressure, after filtration, and dried under vacuum to give 4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)-N-(4-((R)-4-(4-(2-hydroxyethyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide (EXAMPLE 13, STEP 2, 0.41 g) which was used in the preparation of EXAMPLE 13, STEP 3 without further purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.[CH3:26][O:27][C:28](=[O:34])[CH:29](O)[CH:30]([CH3:32])[CH3:31].CO>C(OCC)(=O)C>[CH3:26][O:27][C:28](=[O:34])[CH:29]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)C(O)C(C)C
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(C)C

Procedure:
Following the procedures of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol and 2-hydroxy-3-methyl-butyric acid methyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give racemic 3-Methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid methyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=3.70 min, [M+H]+=466
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[CH3:18][CH:19]([N:22]1[C:26](=[O:27])[N:25]([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:40]4[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=4)[CH2:36][CH2:35]3)=[N:32][CH:33]=2)[CH:24]=[N:23]1)[CH2:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:18][CH:19]([N:22]1[C:26](=[O:27])[N:25]([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:35][CH2:36][N:37]([C:40]4[CH:41]=[CH:42][C:43]([O:46][CH2:11][C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])([OH:10])[CH2:12][N:13]5[CH:17]=[N:16][CH:15]=[N:14]5)=[CH:44][CH:45]=4)[CH2:38][CH2:39]3)=[N:32][CH:33]=2)[CH:24]=[N:23]1)[CH2:20][CH3:21]
Reactant: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)nc2)c1=O
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC(O)(Cn5cncn5)c5ccc(Cl)cc5Cl)cc4)CC3)nc2)c1=O

Procedure:
A mixture of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.3 g, 1.1 mmole), 2-(2-butyl)-4-(2-[4-(4-hydroxyphenyl)piperazin-1-yl]pyridin-5-yl)-1,2,4-triazolin-3-one (see Preparation 5) (0.263 g, 0.67 mmole) and cesium carbonate (0.29 g, 0.89 mmole) in DMF (15 ml) was heated at 80° for 6 hours. The solvent was removed by concentration under reduced pressure and the residue was azeotroped with xylene (2×20 ml) under reduced pressure. The resulting material was partitioned between methylene chloride and water, the aqueous phase separated and re-extracted with methylene chloride. The combined organic extracts were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The residual material was purified by flash chromatography on silica gel eluting with methylene chloride (97):methanol (3):0.88 ammonia solution (1). The product obtained, after collection and evaporation of appropriate fractions, was further purified by flash chromatography on silica gel eluting with methylene chloride (94.5):methanol (5.5):0.88 ammonia solution (4.5). The resulting material obtained, after collection and evaporation of appropriate fractions, was triturated with hexane to yield the desired product, m.p. 84°-87° (0.16 g, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:24]([C:29]1[N:8]([CH2:9][CH:10]2[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:22])[O:20][CH3:21])=[CH:3][C:2]=2[N:1]=1)([CH3:28])([CH3:25])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl (3-amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)carbamate (185 mg, 0.590 mmol) and DMAP (15 mg, 0.118 mmol) were dissolved in 10 mL of DCM. Trimethylacetyl chloride (0.080 mL, 0.649 mmol) was added dropwise and the solution was stirred at rt for 2 h. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The solvent was concentrated. The residue was dissolved in 4 mL of DCE and P2O5 (catalytic) was added and the solution was heated at 125° C. for 1 h using a Personal Chemistry microwave apparatus. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 50 to 75% EtOAc/hexanes. Yield: 122 mg (54%); 1H NMR (400 MHz, CHLOROFORM-D): δ 1.43-1.52 (m, 2H), 1.55 (s, 9H), 1.57-1.66 (m, 2H), 1.67-1.74 (m, 2H), 2.08-2.18 (m, 3H), 3.79 (s, 3H), 4.19 (d, J=7.42 Hz, 2H), 6.63 (br.s, 1H), 7.23 (d, J=8.79 Hz, 1H), 7.37-7.46 (m, 1H), 7.62 (d, J=1.76 Hz, 1H).
Reaction SMILES: C(O)C.C([O:6][C:7](=O)[CH:8]([CH3:23])[CH:9]([N:11]([C:15]1[C:20]([NH2:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=1)[CH:12]1[CH2:14][CH2:13]1)[CH3:10])C>C(O)(=O)C>[Cl:22][C:17]1[N:18]=[CH:19][C:20]2[NH:21][C:7](=[O:6])[CH:8]([CH3:23])[CH:9]([CH3:10])[N:11]([CH:12]3[CH2:14][CH2:13]3)[C:15]=2[N:16]=1
Reactant: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1N)C1CC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1C(=O)Nc2cnc(Cl)nc2N(C2CC2)C1C
Yield: 89.1 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 0.616 g of the (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopropyl-amino]-2-methyl-butyric acid ethyl ester (V-46), prepared in the previous step, was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, water and then dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure. Trituration of the residue with ether, provided 0.468 g of (rac)-2-chloro-9-cyclopropyl-7,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-46).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.F[C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CCCNC1
Reactant: COC(=O)c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccccc1N1CCCC(C(=O)NCc2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 160 °C
Reaction time: 6 h
Yield: 3.9 %

Procedure:
N-[[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]methyl]piperidine-3-carboxamide hydrochloride (198 mg, 0.513 mmol) and methyl 2-fluorobenzoate (0.0653 mL, 0.513 mmol) were dissolved in dimethylsulfoxide (5 mL). To this solution, potassium carbonate (142 mg, 1.03 mmol) was added and the mixture was stirred for 6 hours at 160° C. Subsequently, the mixture was allowed to cool and water was added. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=5:1->1:1) gave 9.80 mg (4%) of the desired compound as a colorless oil.