Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].Cl.O1CCOCC1>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[C:26]([F:25])[CH:27]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cnc(Cl)nc1-c1c(-c2cccc(Br)c2)nn2ccccc12
Reactant: Nc1cccc(F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Fc1cccc(Nc2ncc(F)c(-c3c(-c4cccc(Br)c4)nn4ccccc34)n2)c1
Temperature: 180 °C
Yield: 76.9 %

Procedure:
A solution 2-(3-bromophenyl)-3-(2-chloro-5-fluoro-4-pyrimidinyl)pyrazolo[1,5-a]pyridine (100 mg, 0.25 mmol, obtained from composite batches) in 2-propanol (5 mL) was added 3-fluoroaniline (166 mg, 1.4 mmol) followed by 4M HCl/dioxane (0.4 ml, 1.6 mmol). The reaction mixture was heated at 180° C. in the microwave for 1 h. The solvent was removed under reduced pressure and the solids were recrystallized from EtOAc/hexanes to afford the desired product (92 mg, 77%) as a brown solid. ESIMS (M+H)+=478.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]([CH3:29])[CH:24]([CH3:28])[C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[Br:30][C:31]1[CH:36]=[C:35]([NH2:37])[N:34]=[C:33]([NH2:38])[CH:32]=1.CN1C(=O)CCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[N:23]([CH:24]([C:25](=[O:27])[NH:38][C:33]1[CH:32]=[C:31]([Br:30])[CH:36]=[C:35]([NH2:37])[N:34]=1)[CH3:28])[CH3:29])([CH3:17])([CH3:18])[CH3:19]
Reactant: Nc1cc(Br)cc(N)n1
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C(=O)Nc1cc(Br)cc(N)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
N,N′-dicyclohexylcarbodiimide (24.7 g, 120 mmol) is added slowly to a mixture of 2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid (39 g, 192 mmol) in DCM (60 ml) with ice bath cooling. Stirring is continued and the mixture warmed to RT. The mixture is stirred at RT for 30 minutes before 4-bromopyridine-2,6-diamine A (15 g, 80 mmol) in 60 ml DCM and 10 ml NMP is added dropwise. After stirring for 3 days at RT the reaction mixture is diluted with DCM, filtered and extracted with a saturated aqueous sodium hydrogencarbonate solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 19.8 g (67%). HPLC-MS: M+H=373/375; tR=0.93 min (Method—2).
Reaction SMILES: ClC1C(N(C(=O)COS(C)(=O)=O)C)=CC=C(Cl)C=1CO[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.NC1C=C(C2C=CC(C(N(C)C)=O)=CC=2)C=CC=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:14]=1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)COS(C)(=O)=O)c3Cl)c2n1
Agent: CN(C)C(=O)c1ccc(-c2cccc(N)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2ccccc2n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
A mixture of 8-[2,6-dichloro-3-(N-methanesulfonyloxyacetyl-N-methylamino)benzyloxy]-2-methylquinoline (110 mg), 4-(3-aminophenyl)-N,N-dimethylbenzamide (60.2 mg) and potassium carbonate (94.2 mg) in N,N -dimethylformamide (1 ml) was stirred for 12 hours at 60° C., and ethyl acetate and water were added thereto. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:methanol=20:1, V/V) to give 8-[2,6-dichloro-3-methylamino]benzyloxy]-2-methylquinoline (30 mg) as colorless amorphous.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CC[N:34](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH2:34])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol) in dry CH2Cl2:DMF (2.0:0.1 mL), added DIEA (24 μL, 0.14 mmol) and PyBOP® (40 mg, 0.077 mmol). After stirring the mixture at RT for 15 minutes, ammonia was bubbled through the solution for 15 minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by ammonia bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamide. (27 mg, 0.066 mol, 47%).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1>N1C=CC=CC=1>[C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:16][C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Yield: 76.2 %

Procedure:
A mixture of 4-phenylbenzaldehyde (5.17 g, 28.4 mmol), malonic acid (4.0 g), pyridine (20 ml), and piperidine (0.5 ml) was heated until gas evolution began. Heating was continued until gas evolution ceased (about 30 minutes at 90°-100° C.). The mixture was cooled, and the solid product triturated with boiling methanol (150 ml) and enough concentrated HCl to make the mixture acidic. The mixture was cooled, and the product collected by filtration, washed with water and methanol, and dried in vacuo to provide 4-phenylcinnamic acid (4.85 g, 76% yield), mp 220°-225° C. This material was dissolved in ethanol (150 ml) containing concentrated sulfuric acid (0.5 ml) and triethyl orthoacetate (3.5 ml), and refluxed for 24 hours. Removal of the solvent and recrystallization of the residue from methanol-water provided the ethyl ester (5.0 g, 92% yield), mp 88°-89° C.
Reaction SMILES: C1([CH2:4][NH:5][CH2:6]C2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.CNC.C1COCC1.[BH3-]C#N.[Na+]>>[CH3:4][N:5]([CH3:6])[CH2:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([B:39]2[O:38][C:37]([CH3:52])([CH3:36])[C:41]([CH3:43])([CH3:42])[O:40]2)[CH:45]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of dimethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 23 mg of crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 5.4 mg of the title compound (16%).
Reaction SMILES: [OH:1][C:2]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11](O)=[O:12])[C:7]1([CH3:15])[CH3:14])([C:4]#[CH:5])[CH3:3].[Cl-].[NH4+].F[B-](F)(F)F.[N:23]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][C:2]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([NH2:23])=[O:12])[C:7]1([CH3:15])[CH3:14])([C:4]#[CH:5])[CH3:3]
Reactant: C#CC(C)(O)C1CC(CC(=O)O)C1(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC(C)(O)C1CC(CC(N)=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a mixture of Example 29A (84 mg, 0.4 mmol), ammonium chloride (32 mg, 0.6 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (154 mg, 0.48 mmol) in N,N-dimethylformamide was added N,N-diisopropylethylamine (348 μL, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. It was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine twice, dried (MgSO4), filtered and concentrated in vacuo to provide the title intermediate as a white solid (50 mg, 60% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][C:15]=3[N:16]=1)[CH:6]=[CH:5]2.[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH-].[K+].C(O)CCC>O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][C:15]=3[N:16]=1)[CH:6]=[CH:5]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCI
Reactant: CCCCc1ccc2oc(-c3ccc4cc(O)ccc4c3)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCOc1ccc2cc(-c3nc4cc(CCCC)ccc4o3)ccc2c1
Yield: 56.6 %

Procedure:
In a 30ml round-bottom flask, 0.47 g (1.48 m mole) of 2-(6-hydroxy-2-naphthyl)-5-butylbenzooxazole, 0.43 g (1.79 m mole) of octyl iodide, 0.12 g (1.82 m mole) of potassium hydroxide and 5 ml of butanol were placed, followed by refluxing for 310 minutes. The reaction mixture was poured into water, extracted from ethyl acetate to obtain an organic layer. The organic layer was washed with water dried with mirabilite and dried under reduced pressure to obtain a resultant. The resultant was recrystallized from ethylacetate to obtain a crystal. The crystal was filtered, purified by silica gel column chromatography (eluent: toluene) and recrystallized from acetone to obtain 0.36 g of 2-(6-octyloxy-2-naphthyl)-5-butylbenzooxazole (Yield: 56.6%). ##STR190##
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:15][CH2:16][CH2:17][CH3:18])[CH2:5]C1C=C2C(=CC=1)NC=C2.ClCC1N=C(C2C=CC(C(F)(F)F)=CC=2)OC=1C>>[CH2:16]([O:15][CH:4]([CH3:5])[C:3]([OH:19])=[O:2])[CH2:17][CH3:18]
Reactant: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Agent: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Product: CCCOC(C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid methyl ester (preparation 6) was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole to give rac-3-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl methyl]-1H-indol-5-yl}-2-propoxy-propionic acid as light yellow solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:10]([O:12][C:13](=[O:16])[CH2:14][NH2:15])[CH3:11].CC([O-])=O.[Na+].C([BH3-])#N.[Na+]>CCO>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][NH:15][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11]
Reactant: CCOC(=O)CN
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCO
Product: CCOC(=O)CNCc1ccccc1
Yield: 91.7 %

Procedure:
To a solution of benzaldehyde (14.0 g, 0.132 mol) in absolute EtOH (500 mL) was added glycine ethyl ester hydrochloride (37.0 g, 0.256 mol), NaOAc (32.5 g, 0.396 mol) and sodium cyanoborohydride (9.8 g, 0.158 mol), and the resulting mixture heated to reflux. After 1 hr at reflux, the reaction was cooled and concentrated in vacuo. The residue was taken up into 1N NaOH and EtOAc. The layers were separated and the organic phase was washed with 1N NaOH, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was taken up into EtOAc (150 mL) and treated with gaseous HCl. The resulting solid was collected, washed with Et2O and dried to provide 23.4 g of compound 701 as the HCl salt. ##STR80##
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:48]([O:55][C:56]([N:58]1[CH2:62][CH:61]([CH2:63][O:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[C:67]([F:72])[CH:66]=2)[CH:60]2[N:73]([C:76](=[O:83])[CH:77]([NH2:82])[C:78]([CH3:81])([CH3:80])[CH3:79])[CH2:74][CH2:75][CH:59]12)=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:48]([O:55][C:56]([N:58]1[CH2:62][CH:61]([CH2:63][O:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[C:67]([F:72])[CH:66]=2)[CH:60]2[N:73]([C:76](=[O:83])[CH:77]([NH:82][C:11](=[O:13])[CH:9]([N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:14])[CH3:10])[C:78]([CH3:79])([CH3:81])[CH3:80])[CH2:74][CH2:75][CH:59]12)=[O:57])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)C(N)C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
A solution of Boc-N(Me)Ala-OH (181 mg, 0.89 mmol) in NMP (6 mL) was cooled to 0° C. and treated with HATU (345 mg, 0.91 mmol) and DIPEA (0.20 mL, 1.2 mmol). After 10 min, amine 82 (400 mg, 0.80 mmol) in NMP (5 mL) was added and the reaction mixture was allowed to warm to ambient temperature. After 16 h, the solution was diluted with EtOAc, washed successively with 1M HCl, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated to give 83 (546 mg) as an off-white foam that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.37-7.29 (m, 5H), 7.01 (app q, J=9.3 Hz, 1H), 6.66 (m, 1H), 6.53 (m, 1H), 5.19-5.09 (m, 2H), 4.69 (m, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.49-4.44 (m, 2H), 4.05-3.97 (m, 1H), 3.84-3.77 (m, 1H), 3.48-3.36 (m, 1H), 2.79 (s, 3H), 1.50 (s, 9H), 1.32 (d, J=6.9 Hz, 3H), 0.98 (s, 9H) ppm. Mass spectrum, m/z [687.9] (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:13](O)=[O:14])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.B.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([CH2:13][OH:14])[CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(CO)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.1 %

Procedure:
Under an argon atmosphere 1-(tert-Butoxycarbonylamino-methyl)-cyclopropanecarboxylic acid (3.23 g, 15.0 mmol) was dissolved in THF (50 mL) and cooled to −70 C. Borane tetrahydrofurane complex (1 M in THF, 22.5 mL, 22.5 mmol) was added at −70 C. The mixture was then stirred at 0 C for 2.5 h after which borane tetrahydrofurane complex (1 M in THF, 7.5 mL, 7.5 mmol) was added at 0 C. The mixture was stirred at RT for 1.5 h. Aq. NH4Cl (50 mL) was added at 20 C and the aqueous phase was extracted with EtOAc (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford (1-Hydroxymethyl-cyclopropylmethyl)-carbamic acid tert-butyl ester (2.6 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][CH3:23]>C(#N)C>[CH3:23][O:22][CH2:21][CH2:20][N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 80 °C

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 124d (190 mg, 1.13 mmol) in acetonitrile (10 mL) was added K2CO3 (311.9 mg, 2.26 mmol) and 1-bromo-2-methoxyethane (188.3 mg, 1.36 mmol). The reaction mixture was heated at 80° C. for 17 h under microwave irradiation. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 133a as a white solid (230 mg, 90%), which was used in the next step without further purification. MS-ESI: [M+H]+ 227.0
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:16]=[CH:17][C:18]3[N:23]=[N:22][N:21]([CH2:24][C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[CH:30][CH:29]=[CH:28]5)[C:19]=3[N:20]=2)[CH:12]=[N:11]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([CH2:24][N:21]3[C:19]4[N:20]=[C:15]([C:13]5[CH:12]=[N:11][N:10]([CH2:9][CH2:8][OH:7])[CH:14]=5)[N:16]=[CH:17][C:18]=4[N:23]=[N:22]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: c1cnc2ccc(Cn3nnc4cnc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: OCCn1cc(-c2ncc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-((5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)quinoline (237 mg, 0.520 mmol) and TsOH.H2O (119 mg, 0.624 mmol) in MeOH (15 mL) was stirred for 3 h at room temperature. The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (CH3CN, H2O gradient plus 0.1% AcOH) to afford the title compound, after lyophilization, as a white powder (116 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ 3.72 (dd, 2H, J=10.8, 5.4 Hz), 4.18 (t, 2H, J=5.4 Hz), 4.90 (t, 1H, J=5.3 Hz), 6.06 (s, 2H), 7.47 (m, 1H), 7.76 (m, 1H), 7.93-7.97 (m, 2H), 8.12 (m, 1H), 8.31 (m, 1H), 8.45 (s, 1H), 8.90 (m, 1H), 9.64 (s, 1H); LCMS (APCI) m/z 373.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][C:15]([OH:17])=O)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH2:31])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:31][C:15](=[O:17])[CH2:14][C:10]2[S:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12][C:11]=2[CH3:13])[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1CC(=O)NC1CCCN(C(=O)OC(C)(C)C)C1
Yield: 59 %

Procedure:
Using 2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]acetic acid (1.60 g, 5.99 mmol) and 1-(tert-butoxycarbonyl)-3-aminopiperidine (1.20 g, 5.99 mmol), the same procedure was followed as in Step 1a of Example 1 to give 1.59 g (59%) of the desired compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1c(F)cccc1C(=O)Cl

Procedure:
A solution of 2.87 g of 3-fluoro-2-methylbenzoic acid in 25 ml of thionyl chloride is refluxed for 1.75 hour and the excess thionyl chloride removed under vacuum. To the residue is added toluene (several times) and the toluene removed under vacuum after each addition to give 3-fluoro-2-methylbenzoyl chloride.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=O.[NH2:20][CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1.[BH4-].[Na+]>CO>[CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][NH:20][CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCc2cccnc21
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1c(CNC2CCCc3cccnc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a stirred solution of 1-(2-trimethylsilylethoxymethyl)-2-formyl-benzimidazole (4.26 g, 15.4 mmol) in dry MeOH (50 mL) was added a solution of 8-amino-5,6,7,8-tetrahydroquinoline (2.20 g, 14.8 mmol) in dry MeOH (20 mL) and the mixture stirred for 2 h at room temperature under an argon atmosphere. The reaction mixture was concentrated under reduced pressure and the resultant residue analyzed by 1H NMR to confirm imine formation. The residue was re-dissolved in dry MeOH (80 mL) and to the resultant solution was added sodium borohydride (1.17 g, 30.8 mmol). The mixture was stirred for 5 h, concentrated in vacuo and diluted with CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (125 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (2×75 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude material through a plug of silica gel (CH2Cl2/MeOH 96:4) afforded the desired amine (5.91 g, 98%) as an orange oil. 1H NMR (CDCl3) δ −0.07 (s, 9H), 0.90 (t, 2H, J=9 Hz), 1.72-1.83 (m, 2H), 1.95-2.01 (m, 1H), 2.76-2.85 (m, 2H), 3.54 (t, 2H, J=9 Hz), 4.33 (m, 2H), 5.68 (d, 1H, J=12 Hz), 5.75 (d, 1H, J=12 Hz), 7.05-7.09 (m, 1H), 7.25-7.30 (m, 2H), 7.38 (d, 1H, J=9 Hz), 7.44-7.46 (m, 1H), 7.71-7.73 (m, 1H), 8.36-8.38 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:10]2)[C:5]([Cl:20])=[CH:4][N:3]=1.CC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]#[N:34]>>[C:33]([CH2:32][N:15]([C@@H:11]1[CH2:12][CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([Cl:20])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)[S:16]([CH3:19])(=[O:18])=[O:17])#[N:34]
Reactant: CS(=O)(=O)N[C@@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CS(=O)(=O)N(CC#N)[C@@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
rel-N-[(1R,3R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (400 mg, 1.18 mmol) was dissolved in acetone (15.0 mL, 204 mmol) and cesium carbonate (576 mg, 1.77 mmol) was added. After 15 min, bromoacetonitrile (130 uL, 1.86 mmol) was added and the mixture stirred at room temperature for 4 days. LCMS analysis showed that the reaction had only gone to 50% completion. A second aliquot of bromoacetonitrile (90.4 uL, 1.30 mmol) was added and the reaction was heated at 45° C. overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in DCM (30 mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain rel-N-cyanomethyl-N-[(1R,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide as a white foam (261 mg, 58%). LCMS (m/e) 378 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 5.32 (d, 1H, J=7.3 Hz), 4.34-4.07 (m, 3H), 3.97-3.85 (m, 1H), 3.08 (s, 1H), 2.49-2.39 (m, 1H), 2.17-2.08 (m, 1H), 2.03-1.94 (m, 2H), 1.62-1.45 (m, 3H), 1.30-1.15 (m, 1H).