Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(C(N)=O)[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+].CC#[N:48]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:48])[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: NC(=O)C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Temperature: 25 °C

Procedure:
To a solution of Compound [XXXIV] (8.40 g, 26.9 mmol, 1.0 eq.) in CH3CN (26 mL) and water (26 mL) was added [bis(trifluoroacetoxy)iodo]benzene (17.4 g, 40.4 mmol, 1.5 eq.) and the resulting mixture stirred at room temperature. After 16 hours the reaction was slowly poured into NaHCO3 (aq sat) and extracted with ethyl acetate (×3). The combined organic layers were dried, concentrated, and the residue purified by silica gel chromatography by eluting with CHCl3 to CHCl3/MeOH/NH4OH (95:5:1) to give Compound [XXXV]: 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 2.40-2.50 (m, 2H) 2.73-2.82 (m, 2H) 3.77-3.85 (m, 2H) 3.85-3.93 (m, 2H) 7.37-7.44 (m, 2H) 7.45-7.52 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:22]([CH3:24])[CH3:23].O>CN(C)C=O>[CH:22]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])([CH3:24])[CH3:23]
Reactant: CC(C)Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC(C)C)c1

Procedure:
A solution of methyl 3-hydroxy-4-nitrobenzoate (5.9 g) in dimethylformamide (40 mL) is treated with potassium carbonate (6.2 g) and 2-bromopropane (3.7 g), and the stirred solution is heated at 60°-65° C. for 4 hours. After cooling, water (100 mL) is added and the solution is extracted with toluene (2×100 mL) The combined organic extracts are dried over magnesium sulfate and evaporated in vacuo, to give methyl 3-isopropoxy-4-nitrobenzoate, in the form of a pale yellow solid (5.9 g), m.p. 46°-48° C.
Reaction SMILES: C[CH:2](C)/[CH:3]=[CH:4]/[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:33][C:34]1[CH:43]=[C:42]([NH:44][CH2:45][CH2:46][NH2:47])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1.C(N(CC)CC)C>C(#N)C>[CH3:33][C:34]1[CH:43]=[C:42]([NH:44][CH2:45][CH2:46][NH:47][C:5](=[O:6])/[CH:4]=[CH:3]/[CH3:2])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1
Reactant: Cc1cc(NCCN)c2ccccc2n1
Reactant: CC(C)/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C/C=C/C(=O)NCCNc1cc(C)nc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
(E)-4-Methylpent-2-enoic acid (190 mg, 1.3 mmol) was mixed together with HBTU (470 mg, 1.3 mmol) and N-(2-methyl-4-quinolyl)ethane-1,2-diamine (250 mg, 1.2 mmol) in acetonitrile (5 ml). Triethylamine (1 mll) was added with stirring at 0° C. over 15 minutes and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure, the residue was dissolved in DCM and washed with a saturated solution of sodium bicarbonate. The combined aqueous solutions were extracted three times with DCM. The organic layers were combined, dried over sodium sulfate, the solvent was removed under reduced pressure to give 245 mg of a yellow solid (0.82 mmol, 66%). MS (APCI) m/z=298.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[CH:32]([NH:35][CH:36]([CH3:38])[CH3:37])([CH3:34])[CH3:33]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:35]([CH:36]([CH3:38])[CH3:37])[CH:32]([CH3:34])[CH3:33])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CC(C)NC(C)C
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(C(C)C)C(C)C

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and diisopropylamine.
Reaction SMILES: [C:1]([OH:9])(=O)[C@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3].Cl.[NH2:11][CH2:12][C:13]#[N:14].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O.CCCCCC>[C:12]([CH2:13][NH:14][C:1](=[O:9])[C@@H:2]([OH:3])[CH2:4][CH:5]([CH3:6])[CH3:7])#[N:11]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: N#CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)C[C@H](O)C(=O)NCC#N
Temperature: 0 °C
Reaction time: 18 h

Procedure:
L-leucic acid (85 g, 0.643 mole), amino acetonitrile hydrochloride (68 g, 0.734 mole, 1.14 eg), pyBOP (319 g, 0.612 mole, 0.95 eg) were mixed together in DMF (1 L) and cooled at 0° C. Triethylamine (149 g, 1.47 mole, 2.4 eg) was added dropwise at a rate to maintain internal temperature ≦20° C. Reaction mixture was then allowed to warm to room temperature and stirred for 18 hours. Reaction mixture was poured portionwise into saturated NaHCO3 (4 L) and extracted with EtOAc (2×1 L). Half saturated NaCl solution was added to help partition. Combined organic fractions were washed with brine, 0.5 N HCl, brine, dried and evaporated to give a dark red oil. The latter was passed through a silica plug with 50% EtOAc/hexane to give of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[H-].[Na+].Br[CH:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]1=[O:24]>O1CCCC1>[CH:18]1([N:15]2[CH2:16][CH2:17][CH:13]([S:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:14]2=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: O=C1C(Br)CCN1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C(Sc2ccc(Cl)cc2Cl)CCN1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Place 2,4-dichloro-benzenethiol (728 mg, 4.1 mmol) in tetrahydrofuran (10 mL) and cool to 0° C. Slowly add sodium hydride (98 mg, 4.1 mmol) and stir for 30 minutes. To this solution, add a solution of 3-bromo-1-cyclohexyl-pyrrolidin-2-one (Preparation 1) in tetrahydrofuran (2 mL) and stir at room temperature for 30 minutes. Pour reaction mixture onto ice and extract with methylene chloride. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (20-30% ethyl acetate in hexane) to yield 641 mg (92%) of the title compound: Mass spectrum (apci) m/z=344.1 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]4[CH2:32][CH2:31]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH:30]1([C:26]2[CH:27]=[C:28]([CH3:29])[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][C:2]5=[O:7])=[N:14][CH:13]=4)=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=2)[CH2:31][CH2:32]1
Reactant: O=C1CCCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCCC3=O)nc2)CC1
Yield: 38.3 %

Procedure:
Using piperidin-2-one (14 mg) and (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (50 mg) described in Preparation Example 144 and by the reaction and treatment in the same manner as in Example 1, the title compound (20 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C)C=O.[CH2:17]([NH:24][CH2:25][CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.O1CCCC1.O>[CH2:17]([N:24]([CH2:25][CH2:26][OH:27])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[C:3]=1[F:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(O)c1cccc(Br)c1F
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=C(c1cccc(Br)c1F)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of 3-bromo-2-fluorobenzoic acid (10.0 g, 45.9 mmol) and N,N-dimethylformamide (0.100 ml) in thionylchloride (10 ml) was stirred for 3 hr at 85° C., and the solvent was evaporated under reduced pressure. The residue was added to a solution of N-benzylethanolamine (6.94 g, 45.8 mmol) and triethylamine (9.60 ml, 68.9 mmol) in tetrahydrofuran (140 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (11.5 g, 68.9%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1.[H-].[Na+].Br[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30].O>CN(C=O)C.CCOC(C)=O>[CH2:27]([N:28]([CH2:31][CH3:32])[CH2:29][CH2:30][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:8]2[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=[C:7]2[C:3]2[C:2]([NH2:1])=[N:6][O:5][N:4]=2)=[CH:17][CH:18]=1)[CH3:26]
Reactant: Nc1nonc1-c1nc2cnccc2n1-c1ccc(O)cc1
Reactant: CCN(CC)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(-n2c(-c3nonc3N)nc3cnccc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16.4 %

Procedure:
To a solution containing 50 mg the product from Example 38 (0.17 mmols) in 3.4 mL of dry DMF was added 14 mg of NaH (0.34 mmols, 60% suspension in oil). After stirring at ambient temperature for 5 min, 44 mg of 2-bromoethyl-diethylamine (0.17 mmols) was added to the reaction. The reaction was warmed to 60° C. for 16 h. After cooling to room temperature, 1 mL of water was carefully added to the reaction mixture. The mixture was diluted with 20 mL of EtOAc and washed with 2N NaOH (3×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in a minimum volume of DMSO and filtered through a 0.45 m acrodisc filter. The resulting solution was purified on the Gilson reverse-phase HPLC. The resulting product was dissolved in a minimum amount of MeOH and treated with excess 1 N HCl in diethylether. The resulting precipitate was collected and washed with diethylether to afford the title product (11 mg, 17%). MS (ES+) m/e 393 [M]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[CH:18]=[C:17](I)[CH:16]=[C:15]([Cl:20])[CH:14]=1.C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:13]1[CH:18]=[C:17](/[CH:8]=[CH:7]/[C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:16]=[C:15]([Cl:20])[CH:14]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(/C=C/c2cc(Cl)cc(Cl)c2)c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 3-nitrostyrene (4.6 ml), 1,3-dichloro-5-iodobenzene (7.8 g), palladium(II) acetate (0.20 g), tetrabutylammonium chloride (8.4 g) and sodium bicarbonate (6.3 g) in N,N-dimethylformamide (40 ml) was stirred at 110° C. for 4 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 1,3-dichloro-5-[(E)-2-(3-nitrophenyl)vinyl]benzene (7.93 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:22][CH2:23][C:24]([NH:27][S:28]([C:31]1[CH:32]=[N:33][CH:34]=[C:35](Br)[CH:36]=1)(=[O:30])=[O:29])([CH3:26])[CH3:25]>>[OH:22][CH2:23][C:24]([NH:27][S:28]([C:31]1[CH:32]=[N:33][CH:34]=[C:35]([C:21]#[C:20][C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)[CH:36]=1)(=[O:30])=[O:29])([CH3:26])[CH3:25]
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (147 mg, 0.5 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (155 mg, 0.5 mmol) (example B.2) according to general procedure II. Obtained as a yellow solid (137 mg, 52%). MS (ISP) 522.2 [(M+H)+]; mp 230-231° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][S:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:22])[C:19]([CH3:21])([CH3:20])[O:18][BH:17][O:16]1.C(N(CC)CC)C.O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:15]1([CH3:22])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][S:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:16]1
Reactant: Brc1ccc(N2CCSCC2)cc1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OB(c2ccc(N3CCSCC3)cc2)OC1(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To a mixture of 4-(4-bromophenyl)thiomorpholine (0.40 g), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.40 g) and triethylamine (0.65 mL) in 1,4-dioxane (15 mL) was added dichlorobis(triphenylphosphine)palladium(II) (0.054 g) under argon atmosphere. The reaction mixture was stirred at 100° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.40 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.C([Li])CCC.[CH3:19][Si:20]([CH3:59])([CH3:58])[CH2:21][CH2:22][O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][O:34][C:35]1[C:44]2[C:39](=[CH:40][C:41]([Cl:48])=[C:42]([N:45]=[C:46]=[O:47])[CH:43]=2)[NH:38][C:37](=[O:49])[C:36]=1[C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[CH:51]=1)=[O:25]>>[CH3:58][Si:20]([CH3:19])([CH3:59])[CH2:21][CH2:22][O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][O:34][C:35]1[C:44]2[C:39](=[CH:40][C:41]([Cl:48])=[C:42]([NH:45][C:46]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:12][CH3:13])[C:6]3[CH:11]=[N:10][CH:9]=[CH:8][N:7]=3)=[O:47])[CH:43]=2)[NH:38][C:37](=[O:49])[C:36]=1[C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[CH:51]=1)=[O:25]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N=C=O)c(Cl)cc3[nH]c2=O)c1
Reactant: COC(CNc1cnccn1)OC
Agent: [Li]CCCC
Product: COC(CN(C(=O)Nc1cc2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl)c1cnccn1)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
To a solution of (2,2-dimethoxyethyl)-pyrazin-2-yl-amine (103 mg in 3 mL dry tetrahydrofuran) at -78° C. was added 0.23 mL of a 2.5M solution of butyllithium and the mixture stirred for 30 minutes. At this time, a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-isocyanato-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid 2-trimethylsilanylethyl ester (94 mg in 2 mL tetrahydrofuran) was added via cannula and the mixture warmed to room temperature. After 20 hours, the reaction was quenched by the addition of saturated ammonium chloride and extracted with chloroform. The organic portion was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by preparative tlc on silica gel (ethyl acetate) gave the title compound (11 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:39]([O:38][CH:34]([O:35][CH2:36][CH3:37])[C@@H:33]([N:21]([CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:16])[CH3:42])[CH3:41])[CH3:40]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid VI-10) 94 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)-propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH:1]([N:4]([CH:23]([CH3:25])[CH3:24])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][C:15]=1[OH:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH2:28])[CH3:27].C([BH3-])#N.[Na+]>CO>[CH:23]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[C:18]([CH2:20][NH:28][CH2:26][CH3:27])[CH:17]=[CH:16][C:15]=1[OH:22])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:25])[CH3:24]
Reactant: CCN
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=O)ccc1O)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNCc1ccc(O)c(C(CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-N,N-Diisopropyl-3-(5-formyl-2-hydroxyphenyl)-3-phenylpropanamine (prepared in Example 7.1) (1.23 g, 3.62 mmol) was dissolved in methanol (20 mL). Ethylamine [3.62 mL, 21.7 mmol (6M hydrochloric acid in methanol)] and sodium cyanoborohydride (0.14 g, 2.17 mmol) were added. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was chromatographed on silica (toluene-ethyl acetate-triethylamine 7:3:1). The product was dissolved in diethyl ether and hydrogen chloride in diethyl ether was added. The resulting oil was stirred in diethyl ether over night to give crystals. Yield 0.70 g (44%); mp. 140-142° C.; [α]D−5.0° (c=0.5, methanol); 1H NMR (CD3OD) δ1.30 (m, 15H), 2.59 (m, 2H), 3.05 (m, 4H), 3.70 (m, 2H), 4.07 (s, 2H), 4.42 (t, 1H), 6.85 (d, 1H), 7.20 (m, 2H), 7.30 (t, 2H), 7.41 (d, 2H), 7.50 (s, 1H) Anal. (C24H36N2O*2.0 HCl*0.5H2O) C,H,N.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[CH:7]2.Cl.Cl[CH2:23][CH2:24][N:25]([CH2:27][CH2:28]Cl)[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)CCC>[CH3:26][N:25]1[CH2:27][CH2:28][N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][C:8]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[CH:7]3)[CH2:23][CH2:24]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCCCO
Product: CN1CCN(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A solution of 8-amino-3-phenylsulfonylquinoline (D5) (38.8 g, 137 mmol) in n-butanol (360 ml) was treated with bis-(2-chloroethyl)-methyl-amine hydrochloride (40 g, 138 mmol) and sodium carbonate (72 g, 0.68 mol). The mixture was heated to a vigorous reflux (˜100° C.) for 16 h then a further portion of bis-(2-chloroethyl)-methyl-amine hydrochloride (25 g, 86 mmol) introduced and heating continued for a further 4 h. The solution was cooled and a 1:1 mixture of saturated aqueous sodium bicarbonate and aqueous 10% sodium thiosulphate solution (2 L) added. Stirring was continued at ambient temperature for 16 h then the aqueous phase was extracted with dichloromethane (3×500 ml), the combined organic phase dried over magnesium sulphate, evaporated in vacuo and subjected to chromatography on a Biotage Flash 75 apparatus (1 kg Silica gel) to afford the title compound (E1) as the free base form (11.6 g), identical spectroscopically to that prepared by the first method.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1Br.[OH:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:19]1[CH2:20][CH2:21][CH:17]([OH:16])[CH2:18]1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(Br)c1
Reactant: OC1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: OC1CCN(c2cc(C(F)(F)F)ccc2C(F)(F)F)C1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2,5-bis(trifluoromethyl)phenyl bromide (4.45 g), 3-hydroxypyrrolidine (1.2 g), palladium(II) acetate (0.16 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.87 g) and cesium carbonate (13.6 g) in toluene (74 mL) was stirred under an argon gas atmosphere at 80° C. for 16 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10-75:25) to give the title compound (3.79 g, yield 91%) as an orange oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C([O-])([O-])=O.[K+].[K+].FC(F)(F)S(O[CH2:44][CH:45]([F:47])[F:46])(=O)=O>>[F:46][CH:45]([F:47])[CH2:44][N:21]1[CH2:22][C:19]([CH2:23][C:24]#[N:25])([N:17]2[CH:18]=[C:14]([C:12]3[N:11]4[CH:26]=[CH:27][N:28]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)[CH:15]=[N:16]2)[CH2:20]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)F)C4)c3)n2)cn1
Temperature: 45 °C
Yield: 44.9 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 30.0 mg, 0.0694 mmol) in acetonitrile (694 μL, 0.0694 mmol) was added K2CO3 (38.4 mg, 0.278 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (29.7 mg, 0.139 mmol). After heating to 45° C. for 2 hours, the reaction was incomplete and another portion of 2,2-difluoroethyl trifluoromethanesulfonate (20.0 mg, 0.0936 mmol) was added to drive to completion. Purification of the crude reaction mixture by reverse phase HPLC afforded 2-(1-(2,2-difluoroethyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (13.2 mg, 45% yield). MS (apci) m/z=424.2 (M+1-1).