Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[NH2:2][C:3]1[C:4]([C:11]([N:13]=[C:14]([NH2:17])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:30])=[CH:25][CH:24]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.13 g, 0.33 mmol) was added to a solution of 2-[4-(4-aminobutyl)phenoxy]-N,N-bis-(2-hydroxyethyl)acetamide 26 (0.09 g, 0.3 mmol), triethylamine (0.12 mL), and ethanol (1.7 mL). The reaction mixture was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The residue was triturated with water and then purified by flash chromatography (silica gel, 20-10:1:0-0.2 CH2Cl2/methanol/concentrated ammonium hydroxide, v/v) to provide 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)-N,N-bis-(2-hydroxyethyl)acetamide 27 (0.1 g, 64%) as a yellow solid. mp 114-116° C. 1H NMR (300 MHz, CD3OD) δ 1.70 (m, 4H), 2.60 (m, 2H), 3.32 (m, 2H), 3.50 (m, 4H), 3.70 (m, 4H), 4.81 (s, 2H), 6.85 (d, 2H), 7.10 (d, 2H). m/z (ESI): 523 [C22H31ClN8O5+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[S:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:24][NH:25][C:13]([CH:10]2[CH2:9][CH2:8][S:7][CH2:12][CH2:11]2)=[O:15])[CH:21]=[CH:22][CH:23]=1
Reactant: NNc1cccc(Br)c1
Reactant: O=C(O)C1CCSCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NNc1cccc(Br)c1)C1CCSCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
Oxalyl chloride (1.20 mL, 14.2 mmol) was added dropwise to a stirred solution of tetrahydro-2H-thiopyran-4-carboxylic acid (WO2007006732, 2.00 g, 13.7 mmol) in dichloromethane (25 mL). Then, two drops of N,N′-dimethylformamide were added and stirring was continued. After 1.5 hours, the resultant solution was added dropwise over 30 minutes to a stirred, cooled (ice-bath) solution of (3-bromophenyl)hydrazine hydrochloride (3.05 g, 13.7 mmol) and triethylamine (4.20 mL, 30.1 mmol) in dichloromethane (40 mL). After the addition, the mixture was warmed to room temperature and stirred for two hours. The mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 4% aqueous sodium hydrogen carbonate solution, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and the solid was filtered and dried to give the title compound (2.57 g, 60%) as an off-white solid.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[N:9]=1.[NH4+:21].[Cl-:22]>>[ClH:22].[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]=[CH:10][CH:8]1[NH:9][C:3](=[NH:21])[CH2:4][CH2:5][CH2:6][CH2:7]1)([O-:20])=[O:19]
Reactant: COC1=NC(C=Cc2ccccc2[N+](=O)[O-])CCCC1
Reactant: [Cl-]
Reactant: [NH4+]
Product: Cl
Product: N=C1CCCCC(C=Cc2ccccc2[N+](=O)[O-])N1

Procedure:
The product of Example 156 is reacted with ammonium, chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:26]5[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Product: Cc1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccc(C)cc5)cn4)CC3)nc2)cc1
Yield: 42.8 %

Procedure:
Following the procedure of Example 1, crude crystals were obtained from the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol) synthesized in Reference Example 1 and 4-methylphenylboronic acid (163.0 mg, 1.20 mmol). The crude crystals were recrystallized from chloroform-hexane to yield the title compound as pale yellow needles (melting point: 245.0–247.0° C.)(93.0 mg, yield: 42%).
Reaction SMILES: [S-2:1].[Na+].[Na+].C([O-])(=O)C.[Na+].Cl[C:10]1[CH:15]=[CH:14][C:13](Cl)=[CH:12][CH:11]=1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[CH:19]=1>CN1C(=O)CCC1.O>[C:10]12[S:1][C:12](=[CH:13][CH:14]=[CH:15]1)[CH:11]=2.[C:18]12[S:1][C:21]([CH:22]=[CH:23]1)=[CH:20][CH:19]=2
Reactant: Clc1ccc(Cl)cc1
Reactant: Clc1cccc(Cl)c1
Reactant: [S-2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1cc2cc(c1)S2
Product: c1cc2ccc1s2
Temperature: 205 °C
Reaction time: 1 h

Procedure:
Sodium sulfide 9 hydrobase 6.005 kg (25 mol), sodium acetate 0.69 kg (98.25 mol) and NMP 4.1 kg are thrown in an autoclave with agitator, heated gradually to 205° C. introducing nitrogen, and water of 3.6 litter is distillated. Next, the reaction vessel is cooled to 180° C., p-dichlorobenzen 3.582 kg (24.4 mol), m-dichlorobenzen 0.188 kg (1.28 mol) and NMP 3.2 kg are added, sealed under nitrogen, heated to 270° C., and thereafter, let react at 270° C. for 2.5 hours. Next, the above is thrown in NMP 10 kg that is heated to 100° C., agitated continuously for about one hour and filtered, and washed three times for 30 minutes with hot water of 80° C. This is filtered, dried for 24 hours at 80° under reduced pressure, to obtain PPS-4 of 5 mol % in m-phenylene sulfide unit to the total of m-phenylene sulfide and p-phenylene sulfide, 180° in crystallization temperature during cooling, 0.5 weight % in chloroform-extractable content and 160 g/10 minutes in MFR.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[N:16]=[C:15]([NH2:17])[N:14]=[C:13]([N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:12]=2)[N:7]=1)=[O:5])C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[CH2:26]([NH:33][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[N:16]=[C:15]([NH2:17])[N:14]=[C:13]([N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:12]=2)[N:7]=1)=[O:5])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1nc(-c2nc(N)nc(N(C)c3ccccc3)n2)no1
Solvent: CCO
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(=O)NCc3ccccc3)n2)n1
Yield: 85 %

Procedure:
3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (prepared in an analogous manner to Example 73, Example 73, 80 mg, 230 μmol), benzylamine (50 μL, 230 μmol) and ethanol (4 mL) were heated under reflux for 4 h. After evaporation of the solvent, the crude residue was loaded onto a 5 g isolute pre-pack silica column in a minimal amount of DCM and eluted with 10-30% ethyl acetate-heptane to give the title compound (79 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[OH:12][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][NH2:15]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:15][CH2:14][CH:13]([OH:12])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc(C)cc1
Reactant: NCC(O)c1ccccc1
Solvent: c1ccccc1
Product: Cc1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture of 4-methylphenylacetone (2.7 g) and 2-hydroxy-2-phenylethanamine (2.5 g) was refluxed in benzene (70 ml) under Dean & Stark conditions for 4h. The solvent was removed under reduced pressure, replaced with methanol (100 ml) and cooled in ice during the portionwise addition of sodium borohydride (3.0 g). The solution was stirred for 2 h, the solvent was evaporated under reduced pressure and the residue was partitioned between water (100 ml) and chloroform (100 ml). The organic extract was dried (MgSO4), the solvent was evaporated and the residual oil was crystallised from hexane to give the title compound (2.1 g) as a 44:56 mixture of diastereoisomers, mp 74°-94°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C)C=O>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:20])[CH3:19]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCCc1cccc2cc[nH]c12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCc1cccc2cc[nH]c12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-(2-hydroxyethyl)indole (2.86 g, 17.7 mmol) in 25 mL of dry dimethylformamide was added imidazole (2.54 g, 37.3 mmol) followed by triisopropylsilyl chloride (4.35 mL, 19.7 mmol) and the mixture stirred at room temperature under nitrogen for 3 hours. After diluting with hexanes (500 mL) the organic layer was washed with water (2×50 mL) and saturated aqueous sodium chloride (1×50 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to provide 7-(2-(triisopropylsilyloxy)eth-1-yl)indole. This indole was reacted essentially as described in Preparation II to provide the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.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:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:13]=[CH:12][C:5]=1[CH2:6][O:7][Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)ccc1CO[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1CO[Si](C)(C)C
Temperature: 70 °C
Yield: 65.1 %

Procedure:
Using General Procedure D; (4-bromo-2-methyl-benzyloxy)-trimethylsilane (Intermediate 134, 550.0 mg, 2.01 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (38.0 mg, 0.20 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.05 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (142.0 mg, 0.20 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (380.0 mg, 65%) was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14](=[O:38])[C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:37])[C@@:21](CC(OCCC)=O)([NH2:29])[CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH-:39].[Li+].[CH2:41]([CH2:44][O:45]C)OC>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14](=[O:38])[C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:37])[C@H:21]([NH:29][CH2:41][C:44]([OH:45])=[O:39])[CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCCOC(=O)C[C@](N)(CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Reactant: COCCOC
Reactant: [OH-]
Agent: [Li+]
Product: Nc1nccc2cc(CNC(=O)[C@@H]3CCCN3C(=O)[C@@H](CC3CCCCC3)NCC(=O)O)ccc12
Reaction time: 3 h

Procedure:
To a solution of 135 mg of N-(1-amino-isoquinolin-6-ylmethyl)-1-(propyloxycarbonylmethyl amino-2(R)-cyclohexylmethyl-acetyl)-prolinamide in 4.0 mL dimethoxyethane was added 2.0 mL of 2 M aqueous lithium hydroxide solution was added and stirring was continued for 3 h at ambient temperature. The solvent was removed i.vac., methanol was added and the compound was purified by reversed-phase column chromatography as described in example 110c. Yield: 100 mg (81%). MS: 482
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C[N-]OC.[CH2:15]([Li])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2](=[O:9])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: [Li]CCCCCC
Agent: C[N-]OC
Agent: Cl
Product: CCCCCCC(=O)c1cccnc1

Procedure:
In an example of the general procedure (scheme 1), nicotinoyl chloride hydrochloride (1) is converted to the N-methyl-N-methoxyamide (2) in the presence of a base and reacted with hexyl-lithium (J. Med. Chem., 35, 1992, 2392-2406) to produce 1-pyridin-3-yl-heptan-1-one (3).
Reaction SMILES: OC=CCC[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1.C(Br)(Br)(Br)[Br:19].N1C(C)=C[C:26]([CH3:30])=[CH:25][C:24]=1C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Br:19][C:10]1[CH:11]=[CH:6][C:7]([CH:12]2[O:13][CH2:14][CH2:15][CH2:16][O:17]2)=[CH:8][C:9]=1[CH:24]=[CH:25][CH2:26][CH3:30]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(C)nc(C)c1
Reactant: OC=CCCc1ccccc1C1OCCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC=Cc1cc(C2OCCCO2)ccc1Br
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 14c (6.6 g; 28.2 mmol), freshly sublimed carbon tetrabromide (10.77 g; 32.5 mmol) and anhydrous collidine (4.3 ml; 3.9 g; 32.5 mmol) in dry dichloromethane (135 ml) at -20° C. was added solid triphenylphosphine (10.83 g; 41.3 ml). The reaction was complete within 30 min as demonstrated by thin-layer chromatographic analysis (silica 5% and 50% ethyl acetate in hexanes), and was quenched with the addition of methanol (2 ml) and the solvent removed. The crude mixture was chromatographed on silica (10% ethyl acetate in hexanes) to provide 14d as a colorless oil. (5.93 g; 71% yield). 1H NMR (CDCl3, 500 MHz) δ 7.60 (dd, J=7.5, 1.5 Hz, 1 H, H at C-6, 7.25 (m, 2 H, H at C-4 and C-5), 7.12 (dd, J=7.5, 1.5 Hz, 1 H, H at C-3), 5.92 (dt, J=15.0, 6.5 Hz, 1 H, H at C-3 of butene), 5.71 (m, 1 H, H at C-2 of butene), 5.56 (s, 1 H, H at C-2 of dioxane), 4.24 (dd, J=11.5, 5.0 Hz, 2 H, He at C-4 and C-6 of dioxane), 3.96 (m, 4 H, H at C-4 of butene and Ha at C-4 and C-6 of dioxane), 3.53 (d, J=6.5 Hz, 2 H, H at C-1 of butene), 2.22 (m, 1 H, Ha at C-5 of dioxane), 1.42 (d, J=13.5, 1 H, H at C-5 of dioxane) 13C NMR (CDCl3, 125 MHz) δ 136.5, 134.9 (4o carbons of aromatic ring, 129.8, 129.0, 127.4, 126.7, 126.5, 126.4 (alkene and aromatic C-H's), 100.0 (C-2 of dioxane), 67.6 (C-4 and C-6 of dioxane), 35.2 (C-4 of alkene), 33.2 (C-1 of alkene), 25.8 (C-5 of dioxane) IR 2985, 2860 (aromatic C--H), 1100 (C--O) cm-1 ; Mass Spec. (70 ev) m/z (rel abund 297 (M+ -, 0.5), 217 (M+ -Br, 86), 159 (M+ -C3H7O and Br, 37), 143 (M+ -C3H7O2 and Br, 53), 131 (M+ -1,3 dioxane and Br, 100); HRMS calcd for C14H16BrO2 : M+ -H=297.0317. Found: 297.0340.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.CCN(C(C)C)C(C)C.[NH2:34][CH2:35][CH:36]([CH3:39])[C:37]#[N:38].C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:38][CH2:37][CH:36]([CH3:39])[C:35]#[N:34])[N:8]=1
Reactant: CC(C#N)CN
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)CNc1nccc(-c2c(Br)nc(C3CC3)n2COCC[Si](C)(C)C)n1
Temperature: 90 °C
Yield: 100 %

Procedure:
A solution of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (2.5 g, 5.8 mmol), DIEA (2.0 mL, 11.6 mmol), and 3-amino-2-methylpropanenitrile (1.49 g, 17.7 mmol) in NMP (10 mL) was treated with Na2CO3 (1.23 g, 11.6 mmol) and the resulting reaction mixture heated at 90° C. overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc (75 mL) and water (100 mL). The layers were separated and the organic portion was washed with saturated aqueous NaHCO3 solution (100 mL), brine (150 mL), dried (Na2SO4) and concentrated to a brown residue. Purification by flash chromatography (0-50% EtOAc-heptane) afforded 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)-2-methylpropanenitrile (2.79 g, 5.8 mmol) as a white solid: LCMS (m/z) 477.1 (MH+), tR=0.98 minute.
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29]>CS(C)=O.O>[N:4]1([CH2:3][CH:2]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[O:1][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CCOC(=O)CCCCCBr
Reactant: COc1ccc(COCC(O)Cn2ccnc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
1-[2-Hydroxy-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (20 g, 0.076 mol) was added to a stirred suspension of powdered potassium hydroxide (17 g, 0.30 mol) in dimethylsulphoxide (50 ml) at 18° C. and stirred for 0.5 hours. Ethyl 6-bromohexanoate (33.45 g, 0.15 mol) was then added and the resulting mixture was stirred at 18° C. for 12 hours. The reaction mixture was diluted with water (21) and washed with dichloromethane (2×100 ml), neutralised to pH 6-7 with sulphuric acid (2M) and extracted with dichloromethane (4×150 ml). The combined extracts were dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which by column chromatography (silica gel, 20% methanol in ethyl acetate) gave pure 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoic acid as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([NH:11][C:12](=[O:28])[CH2:13][C:14]2[N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH:17]=[N:16][CH:15]=2)[CH2:8][NH:7][CH2:6]1)=[O:4].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[C:37]([BH3-])#N.[Na+]>CO>[CH2:37]([N:7]1[CH2:8][C@H:9]([NH:11][C:12](=[O:28])[CH2:13][C:14]2[N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=3)[CH:17]=[N:16][CH:15]=2)[CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: [BH3-]C#N
Reactant: COC(=O)[C@@H]1CNC[C@H](NC(=O)Cc2cncn2Cc2ccc(C#N)cc2)C1
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](NC(=O)Cc2cncn2Cc2ccc(C#N)cc2)CN(CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
cis-3-Methoxycarbonyl-5-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetylamino]piperidine (35.3 mg, 0.093 mmol), benzaldehyde (32.5 uL, 0.278 mmol), and sodium cyanoborohydride (17.5 mg, 0.278 mmol) was dissolved in MeOH (2 mL) and stirred overnight at ambient temperature. The solution was concentrated under reduced pressure and chromatographed (silica gel, 0.5-2% MeOH/CH2Cl2 with NH4OH) to give the title compound. 1H NMR (CDCl3) δ 7.62 (d, 2H, J=8 Hz), 7.52 (s, 1H), 7.11-7.31 (m, 7H), 6.99 (s, 1H), 6.25 (br s, 1H), 5.24 (s, 2H), 3.86-3.96 (m, 1H), 3.65 (s, 3H), 3.29 (s, 2H), 2.48-2.83 (m, 8H), 2.13-2.24 (m, 1H), 1.83-1.95 (m, 1H), 1.50-1.65 (m, 1H). FAB MS 486 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:10][C@H:9]1[C:31](=[O:47])[NH:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]2=[O:45])=[CH:35][C:34]=1[F:46])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:31](=[O:47])[NH:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]2=[O:45])=[CH:35][C:34]=1[F:46])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
(2S,4S)-4-(9H-Fluoren-9-ylmethoxycarbonylamino)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg) was dissolved in CH2Cl2 (2 ml) and piperidine (43 μl) was added. The mixture was stirred for 17 h at 25° C. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2->methanol 2N NH3) to yield (2S,4S)-4-amino-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless amorphous solid (96 mg). MH+=417.5
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and methanesulfonyl chloride (Aldrich), to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 424.
Reaction SMILES: [CH3:1][C:2]([C:7]1[O:11][N:10]=[C:9]([CH3:12])[N:8]=1)([CH3:6])[C:3](=[O:5])[CH3:4].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[O:11][N:10]=[C:9]([CH3:12])[N:8]=1)[CH3:6]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)C(C)(C)c1nc(C)no1
Product: Cc1noc(C(C)(C)C(=O)C=CN(C)C)n1

Procedure:
3-Methyl-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-butan-2-one (101 mg, 0.6 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (140 mg) as a yellow oil which was used directly in the next step.