Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH2:26][C@@H:27]2[CH2:31][O:30]C(C)(C)[O:28]2)[N:12]=1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH2:26][C@@H:27]([OH:28])[CH2:31][OH:30])[N:12]=1
Reactant: CC1(C)OC[C@@H](COc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1cc(OC[C@@H](O)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step (0.48 g) in methanol (5 mL)/H2O (0.1 mL) was added pyridinium p-toluenesulfonate (0.12 g) and the mixture was stirred at reflux for 2 h. The reaction mixture was evaporated, suspended in H2O and extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was triturated with DCM to give the title compound as a white solid. Yield: 0.30 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH2:25]([NH-:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:25]([NH:31][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)Cl)c(C)c1C
Reactant: CCCCCC[NH-]
Product: CCCCCCNC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride is reacted with hexylamide to produce 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid hexylamide, m.p. 157°-158° C.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27](O)=[O:28])[CH:24]=[CH:23][S:22]3)[CH2:4][CH2:3][CH2:2]1.[F:30][C:31]([F:39])([F:38])[C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH:1]1([CH2:5][O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([NH:37][C:34]2[S:35][CH:36]=[C:32]([C:31]([F:39])([F:38])[F:30])[N:33]=2)=[O:28])[CH:24]=[CH:23][S:22]3)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C(O)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc(C(F)(F)F)cs1)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 10 (300 mg, 0.714 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (128 mg, 0.785 mmol) in the presence of EDCI hydrochloride (273 mg, 1.428 mmol), DMAP (80 mg, 0.714 mmol) in a mixture of THF and DMF (1:1, 6 mL) to give 27 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.80-1.90 (m, 4H), 1.98-2.08 (m, 2H), 2.66-2.76 (m, 1H), 3.89-3.95 (m, 2H), 7.15-7.25 (m, 3H), 7.40-7.47 (m, 1H), 7.52-7.67 (m, 2H), 7.78 (d, J=15.9 Hz, 1H), 8.00-8.10 (m, 2H), 13.03 (br s, 1H); APCI-MS (m/z) 571.18 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[CH:3]=[N:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cc(Br)cn3)n2)cc1
Product: Nc1ccc(-c2cnn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-pyrazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.11) (0.44 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.22 g, 1.0 mmol) according to the general procedure VI. Obtained as a yellow solid (0.027 g, 6%). MS (ISP) 451.1 [(M+H)+]; mp 206° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:7]=1[NH2:8])[CH2:2][CH2:3][CH3:4].Cl.[C:23](=N)(OC)[CH3:24].C(=O)([O-])O.[Na+]>CO>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:6]2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:23]([CH3:24])=[N:8][C:7]=2[CH:9]=1
Reactant: CCCCNc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: COC(C)=N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCn1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Yield: 89.7 %

Procedure:
To a methanol (5 mL) solution of 2-(2-n-butylaminoanilin-5-yl)benzoxazole (see Working Example 74-2) (300 mg, 1.07 mmol) was added methyl acetimidate hydrochloride (175 mg, 1.60 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were purified by silica gel column chromatography to yield the title compound (293 mg, 90% yield) as white crystals.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([OH:14])=O)[CH2:4]1.C([N:17](CC)CC)C.N>ClCCl>[N+:9]([O-:11])([O:8][C@H:7]1[CH2:6][C@H:5]([C:12](=[O:14])[NH2:17])[CH2:4][C@@H:3]1[O:2][CH3:1])=[O:10]
Reactant: CO[C@H]1C[C@@H](C(=O)O)C[C@@H]1O[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: N
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](C(N)=O)C[C@@H]1O[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a dichloromethane solution (30 mL) of (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylic acid (example 1, 0.13 g, 0.64 mmol) was added triethylamine (0.72 mL, 5.1 mmol) and ethyl chlorofonnate (0.49 mL, 5.1 mmol) at 0° C. The reaction solution was stirred at 0° C. for 1 hour when aqueous ammonia (8.0 mL, 0.10 mol, 28% wt) was added. The reaction was stirred for another 16 hours at 0° C. The aqueous phase was extracted with dichloromethane (2×15 mL). The combined organics were washed with cold 5% sodium bicarbonate (30 mL) and dried over magnesium sulfate. The organics were concentrated in vacuo and purified by column chromatography, affording the title compound as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 2.02 (ddd, J=3.7, 6.1, 14.5 Hz, 1H), 2.22 (dd, J=8.5, 15.3 Hz, 1H), 2.30-2.37 (m, 1H), 2.40-2.47 (m, 1H), 2.94 (quintet, J=6.2 Hz, 1H), 3.44 (s, 3H), 3.89-3.91 (m, 1H), 5.36 (d, J=6.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:8]([C:7]2[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=2[Cl:1])=[O:9])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid (1.93 g, 10 mmol), 4-tert-Butyl-phenylamine (1.49 g, 10 mmol), DIEA (3.5 mL, 20 mmol), and HATU (4.56 g, 12 mmol) were added to DMF (20 mL). The reaction was stirred at rt for 15 h. The resulting dark brown solution was extracted with DCM (2×10 mL), washed with H2O (2×10 mL), and dried over sodium sulfate. The curde product was further purified using Flash Chromatography (2% MeOH/DCM), affording the desired product as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(-c3ccc(F)cc3)ccc2F)c1
Reaction time: 0.03 h

Procedure:
The phenyl bromide (139)(100 mg, 0.25 mmol) was coupled to 4-fluoro-phenylboronic acid (33 mg, 0.23 mmol) using Method E. During this reaction, partial hydrolysis occurred. The residue was extracted using Work-up E1 to give a mixture of acid and ester, which was used without further purification. For the ester: LC/MS tr 1.62 min; MS(ES+) m/z 412 (M+H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[C:10]([Cu])#[N:11].N.C(OCC)C>CN(C=O)C>[F:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:10]#[N:11]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: N#C[Cu]
Agent: N
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of 1-bromo-2-fluoro-4-methylbenzene (70 g, 370 mmol) and CuCN (50 g, 555 mmol) in DMF (300 mL) was heated at reflux for 24 h. After cooling to RT, concentrated aqueous ammonia (300 mL) and diethyl ether (200 mL) were added and the mixture stirred for 1 h. The mixture was extracted with diethyl ether (3×200 mL). The combined organic layers were washed with brine (3×200 mL) and dried over sodium sulfate. Solvent was removed in vacuo to give the product (44 g, 88%) as pale yellow solid. MS (M+H)+ 136.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:17].O>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14]([CH:15]=[O:17])=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nccnc1OCc1ccccc1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1nccnc1OCc1ccccc1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
2-Benzyloxy-3-methylpyrazine (600 mg) was dissolved in 1,4-dioxane (12 mL), selenium dioxide (1 g) and water added (one drop) and the mixture heated at reflux for seventeen hours. The reaction mixture was allowed to cool to ambient temperature, filtered and the solvents removed. The residue was dissolved in water (30 mL), neutralised with aqueous sodium hydrogen carbonate solution (10%) and extracted with dichloromethane (3×40 mL), the organic phase was dried (MgSO4). After removal of the solvents the oil was purified by MPLC (15%ethyl acetate, hexane, silica) to give 2-benzyloxypyrazine-3-aldehyde (460 mg, mp 69.4° C.).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]3[CH:20]=[CH:21][S:22][C:18]=3[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[S:22]1[C:18]2[CH:17]=[CH:16][N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][CH2:10]3)[C:19]=2[CH:20]=[CH:21]1
Reactant: c1ccc(CN2CCC(c3nccc4sccc34)CC2)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(c2nccc3sccc23)CC1
Reaction time: 12 h

Procedure:
1 g of the product obtained in Step E is added dropwise to a suspension of 93 ml of ethyl chloroformate and 0.89 g of K2CO3 in 5 ml of toluene. After 12 hours at ambient temperature, the reaction mixture is diluted with water, extracted with toluene and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 95/5) enables the expected product to be isolated.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]45[CH2:21][CH:16]6[CH2:17][CH:18]([CH2:20][C:14](Br)([CH2:15]6)[CH2:13]4)[CH2:19]5)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[OH:29][C:23]1[CH:28]=[CH:27][C:26]([C:2]23[CH2:9][CH:8]4[CH2:7][CH:6]([CH2:5][C:4]([C:12]56[CH2:21][CH:16]7[CH2:17][CH:18]([CH2:20][C:14]([C:26]8[CH:27]=[CH:28][C:23]([OH:29])=[CH:24][CH:25]=8)([CH2:15]7)[CH2:13]5)[CH2:19]6)([CH2:10]4)[CH2:3]2)[CH2:11]3)=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: BrC12CC3CC(C1)CC(C14CC5CC(CC(Br)(C5)C1)C4)(C3)C2
Solvent: CO
Product: Oc1ccc(C23CC4CC(C2)CC(C25CC6CC(CC(c7ccc(O)cc7)(C6)C2)C5)(C4)C3)cc1
Temperature: 55 °C
Yield: 94.1 %

Procedure:
Into a 10 liter four-necked separable flask equipped with a thermometer, a stirrer, an inlet for nitrogen gas and a reflux condenser, 64.5 g (0.15 moles) of 3,3′-dibromo-1,1′-biadamantane and 1032 g (10.95 moles) of phenol were placed, and the resultant mixture was heated under the refluxing condition at 155° C. for 30 minutes. After the mixture was cooled at the room temperature, 4.3 liters of methanol was added, and the obtained mixture was heated under the refluxing condition at 55° C. for 10 minutes. The formed precipitates were separated by filtration, washed with a flow of methanol and dried at 60° C. under a reduced pressure for 24 hours, and 64.2 g of the product was obtained (the yield: 93.7%).
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]2[C:22]3[CH:21]=[N:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.C([O-])(=[O:25])C.[K+]>C(O)C.O>[NH:12]1[C:13](=[O:25])[CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]1=2
Reactant: Cc1ccc(S(=O)(=O)ON=C2CCCc3ccncc32)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCCc2ccncc2N1
Yield: 27.6 %

Procedure:
A solution of 8-(4-methylphenylsulfonyl)oxyimino-5,6,7,8-tetrahydroisoquinoline (1.2 g) and potassium acetate (7.45 g) in ethanol (25 ml) and water (30 ml) was heated at 95° C. for 23 hours. The solvent was evaporated at reduced pressure, and the residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The dried extract (dried over sodium sulfate) was evaporated at reduced pressure to give crude product. After partial purification by column chromatography (SiO2; 30 g, AcOEt/hexane=2/1, then 5% MeOH—CHCl3), the obtained solid was washed with ether to give 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-2-one (170 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[C:17]([N:19]2[C@H:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][C@H:21]([C:29]([NH:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:30])[CH2:20]2)[CH:16]=[C:15](Cl)[N:14]=1.[C:39]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][C:42]=1[F:50])#[N:40].C([O-])(O)=O.[Na+]>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.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[C:17]([N:19]2[C@H:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][C@H:21]([C:29]([NH:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:30])[CH2:20]2)[CH:16]=[C:15]([C:44]2[CH:45]=[CH:46][C:41]([C:39]#[N:40])=[C:42]([F:50])[CH:43]=2)[N:14]=1
Reactant: COc1ccc(CNc2nc(Cl)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: C1COCCO1
Product: COc1ccc(CNc2nc(-c3ccc(C#N)c(F)c3)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To cis-1-[2-({[2,4-bis(methyloxy)phenyl]methyl}amino)-6-chloro-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (322 mg, 0.58 mmol) and (4-cyano-3-fluorophenyl)boronic acid (124 mg, 0.75 mmol) were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL), and the resulting mixture was purged (“degassed”) with N2 into a sealable tube for 5 minutes. Pd(Ph3P)4 (33.5 mg, 0.029 mmol) was added, and N2 gas was bubbled through the mixture for an additional 5 minutes. The tube was sealed, and the reaction mixture was stirred overnight at 100° C. The reaction mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 50% EtOAc/Hexanes) afforded the title compound (305 mg) as a yellow foam. LC-MS (ES) m/z=641 [M+H]+.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]=[C:2]=[O:1])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(c3ccc(N=C=O)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a dichloromethane (400 mL) solution of diphosgene (74 mmol, 14.8 g) at 0° C. was added a dichloromethane (1100 mL) solution of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine (Formula IIa, 41 mmol, 11.7 g) and triethylamine (93 mmol, 9.4 g) over a period of 3.5 hours. Once the addition was complete, the reaction was stirred in an ice bath for an additional 30 minutes. The reaction solvent was evaporated, the residue dissolved in tetrahydrofuran (300 mL), and the insolubles removed by filtration. The filtrate was concentrated by rotary evaporation to give 4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenylisocyanate as a beige solid (12.8 g, 100% crude yield). The product was advanced to the next reaction step without purification. 1H NMR (400 MHz, CDCl3) δ 7.08-6.85 (m, -Ar), 3.79 (s, 3 H, OCH3), 3.45-3.20 (m, 8 H, CH2).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])([O:13][CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:10]1([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COC1(c2cccc(F)c2F)CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(c2cccc(F)c2F)CCNC1
Yield: 84.7 %

Procedure:
Preparation according to Preparation 15. Tert-butyl-3-(2,3-difluorophenyl)-3-methoxypyrrolidin-1-carboxylate (4.7 g, 15 mmol), methylene chloride (20 mL) and trifluoroacetic acid (5 mL). Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (2.71 g, 85%). MS m/z (rel. intensity, 70 eV) 198 (44), 183 (95), 171 (bp), 141 (61), 127 (44).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)O.N1C=CC=CC=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:2]([F:13])([F:12])[F:1]
Reactant: Oc1ccc(C(O)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Oc1ccc(C(Cl)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (ice bath) mixture of 4-(2,2,2-trifluoro-1-hydroxyethyl)phenol (4.3 g, 22 mmol) and anhydrous pyridine (1.8 ml, 22 mmol) in toluene was added thionyl chloride (SOCl2) (2.3 ml, 31 mmol) drop wise via a syringe. After stirred for 1 h at 0° C., the reaction was heated at 70° C. for 2 h. At this point, reaction did not go completion, indicated by LCMS. Heating was continued for 16 h. Reaction was quenched with ice water. The resulted mixture was diluted with EtOAc. The organic layer was washed with saturated Na2CO3, water and brine. After dried over Na2SO4, the solution was filtered and concentrated. The residue was purified on a silica gel column (5-10% EtOAc/hexane) giving the title compound as a light yellow oil. MS m/z: 21 1(M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[N:27]([CH2:28][CH2:29][O:30][C:31]4[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][C:32]=43)[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]>C(Cl)Cl>[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[C:32]4[CH:35]=[C:36]([S:39]([N:6]5[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]5)(=[O:41])=[O:40])[CH:37]=[CH:38][C:31]=4[O:30][CH2:29][CH2:28][N:27]3[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: CN(C)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCC(N(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl-piperidin-4-yl-amine (45 mg, 0.35 mmol) and NEt3 (83 μL, 0.59 mmol) in DCM (15 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (93 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 1 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-16% MeOH in EtOAc) then freeze-dried from MeCN/H2O affording 131 (29 mg, 52%) as a white solid. LCMS: RT 2.83 min [M+H]+ 486.3. 1H NMR (DMSO, 400 MHz): δ 8.79 (1H, d, J=2.42 Hz), 8.00 (1H, s), 7.93 (1H, d, J=0.62 Hz), 7.63 (1H, dd, J=10.74, 2.40 Hz), 7.26 (1H, d, J=8.62 Hz), 5.72-5.71 (1H, m), 4.61-4.60 (4H, m), 3.60-3.57 (2H, m), 2.40-2.39 (2H, m), 2.15-2.05 (1H, m), 2.10 (6H, s), 1.77-1.73 (2H, m), 1.49 (6H, d, J=6.62 Hz), 1.46-1.37 (2H, m)