Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[O:31])=[N:22][C:21]=1[CH3:32])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:26]2=[O:31])=[N:22][C:21]=1[CH3:32])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: O=CCc1ccccc1
Product: Cc1nc(N2CCCC(CCc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 24 %

Procedure:
Following the procedure as described in Example 3, making variations as required to use 2-phenylacetaldehyde in place of cyclopropanecarbaldehyde to react with N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 24% yield: mp 124-126° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.46-7.09 (m, 10H), 5.98 (t, J=5.4 Hz, 1H), 4.55 (d, J=5.4 Hz, 2H), 4.29-4.20 (m, 1H), 4.07-4.04 (m, 1H), 2.83-2.66 (m, 2H), 2.64 (s, 3H), 2.61-2.48 (m, 1H), 2.41-2.26 (m, 1H), 2.17-2.01 (m, 2H), 1.96-1.76 (m, 2H), 1.74-1.58 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 172.8, 162.7, 156.9, 152.2, 141.3, 137.9, 128.8, 128.5, 128.4, 127.9, 127.6, 126.1, 119.1, 47.9, 44.1, 41.4, 33.3, 33.0, 25.7, 21.3, 17.4; MS (ES+) m/z 434.1 (M+1).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:15][C:16]#[N:17].[K+]>>[C:16]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[NH2:17]
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: N#C[O-]
Agent: [K+]
Product: NC(=O)N[C@@H](CSCc1ccccc1)C(=O)O

Procedure:
The desired compound was synthesized from S-benzyl-L-cysteine (2 g, 9.48 mmol) (Fluka) and potassium cyanate (1.7 g, 21 mmol) by a modification of published protocols [see Coll. Czech Chem. Commun. 33:2918 (1968)]. Instead of isolating the N-carbamyl-S-benzylcysteine intermediate, after an initial reflux of 1 h, 25 ml of 10% hydrochloric acid was added and reflux was continued for 1.5 h. Upon cooling, the desired product precipitated as a white solid 1.7 g (77% yield), melting point 119.5°-120.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:11]1[CH2:12][CH2:13][N:8]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])[CH2:9][CH2:10]1
Reactant: C1COCCN1
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCOCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
2-(2-Chloroethoxy)ethanol (1.25 g, 10 mmol) was added to a mixture of morpholine (2.58 g, 30 mmol) and potassium carbonate (5.5 g, 40 mmol) in acetonitrile (50 ml). The mixture was heated at reflux for 6 hours and then stirred for 18 hours at ambient temperature. The insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10 and then 80/20) to give 2-(2-morpholinoethoxy)ethanol (600 mg, 34%).
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[N:13]([CH:14]=[C:15]([C:21]([O:23]CC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]3[CH:26]=[CH:27][C:28]([CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:29][C:11]=3[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+]>>[N:1]1([CH2:7][CH:8]2[N:13]3[C:12]4[C:26]([C:21](=[O:23])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14]3)=[CH:27][C:28]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:29][C:11]=4[O:10][CH2:9]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=CN1c2ccc(CN3CCOCC3)cc2OCC1CN1CCOCC1)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)OCC2CN1CCOCC1
Temperature: 90 °C

Procedure:
A mixture of 211 mg of the product of Preparation 27 and 274 mg of diethyl ethoxymethylenemalonate is heated under argon at 140° C. for 2 h, then cooled and chromatographed on silica using 2-4% methanol in dichloromethane to provide 230 mg of the intermediate enamide, which is diethyl 2-{[3,7-bis(4-morpholinylmethyl)-2,3-dihydro-4H-1,4-benzoxazin4-yl]methylene}malonate, as an orange foam. This is mixed thoroughly with 1.5 g of polyphosphoric acid, and the mixture is heated at 90° C. for 18 h, then cooled and added to excess aqueous NaHCO3. The mixture is extracted thrice with dichloromethane, and the organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 2-5% methanol in dichloromethane affords 117 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15](C)[C:16](=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][NH:15][CH:12]1[CH2:11][CH2:10][N:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=2)[CH2:14][CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccnc(C#N)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(c2ccnc(C#N)c2)CC1
Reaction time: 2 h

Procedure:
tert-Butyl 1-(2-cyanopyridin-4-yl)piperidin-4-yl(methyl)carbamate (300 mg, 0.949 mmol, 1.0 eq.) was dissolved in DCM (10 ml); TFA (2 ml) was added at 0° C. and stirring was carried out for 2 hours at RT. The reaction mixture was concentrated under reduced pressure, taken up several times in toluene and dried. The crude product was used in the next stage without being purified further.
Reaction SMILES: B(Cl)(Cl)Cl.[CH:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.CS[C:20]#[N:21].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:20]([C:14]1[C:15]2[NH:16][C:17]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)#[N:21]
Reactant: CSC#N
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#Cc1cccc2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To 5.4 ml of a solution of 2.04M of boron trichloride in toluene was added a solution of 1.67 g of carbazole in 10 ml of toluene, and the mixture was refluxed for 1 hr. After cooling, the mixture was treated with 1 ml of methyl thiocyanate and stirred at room temperature for 3 hr. The reaction mixture was poured into 4N aqueous sodium hydroxide under ice-cooling and stirred at 100° C. on an oil bath for 30 min. After cooling, the reaction solution was extracted with methylene chloride, washed with water and dried over anhydrous magnesium sulfate. The residue was chromatographed on a column of silica gel, and the eluate with methylene chloride was discarded. The eluate with 10% acetonitrile-methylene chloride was concentrated, and the product was recrystallized from acetone-ether to give 1.45 g of 1-cyanocarbazole as white crystals melting at 200°-201° C.
Reaction SMILES: O1C2C=CC=CC=2N=C1.NC1C=CC=CC=1.C(OC(=O)[NH:23][C@@H:24]1[CH2:28][CH2:27][N:26]([S:29]([C:32]2[C:40]3[O:39]C(C(C)(C)C)=[N:37][C:36]=3[CH:35]=[CH:34][C:33]=2[Cl:45])(=[O:31])=[O:30])[CH2:25]1)(C)(C)C.OS(O)(=O)=O>O1CCOCC1.O>[NH2:37][C:36]1[C:40]([OH:39])=[C:32]([S:29]([N:26]2[CH2:27][CH2:28][C@@H:24]([NH2:23])[CH2:25]2)(=[O:31])=[O:30])[C:33]([Cl:45])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)C1
Agent: O=S(=O)(O)O
Agent: c1ccc2ocnc2c1
Solvent: C1COCCO1
Solvent: O
Solvent: Nc1ccccc1
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CC[C@@H](N)C2)c1O
Yield: 95.4 %

Procedure:
Following the general procedure for the hydrolysis of the benzooxazole to the desired aniline outlined in example 51, [(R)-1-(2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (2.0 g, 4.31 mmol), water (3.6 mL), and H2SO4 (3.6 mL) in 1,4-dioxane (60 mL) were reacted to afford the title compound (1.2 g, 94%). LCMS m/z 292(M−H)+.
Reaction SMILES: COC1C(OC)=NS(=O)N=1.[CH3:11][N:12]([CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:21][CH2:22][CH2:23][NH2:24])[N:19]=1)[CH3:13].CN(CC1SC=C(CSC[CH2:37][NH:38][C:39]2[C:43](OC)=[N:42][S:41](=[O:46])[N:40]=2)N=1)C.CN>CO>[CH3:13][N:12]([CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:21][CH2:22][CH2:23][NH:24][C:43]2[C:39]([NH:38][CH3:37])=[N:40][S:41](=[O:46])[N:42]=2)[N:19]=1)[CH3:11]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1
Agent: CN
Agent: COC1=NS(=O)N=C1OC
Solvent: CO
Product: CNC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, Step A] is reacted with an equimolar amount of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared in Example 33, Step E] and the resulting 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with methylamine, the title compound is thereby produced.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10]2[N:11]=[C:12]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=4)[N:17]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[N:16]=3)[N:13]=[CH:14][C:9]=2[N:8]([CH3:33])[S:7]1(=[O:35])=[O:34].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[F:24][C:21]1[CH:22]=[C:23]2[C:15]([C:12]3[N:13]=[CH:14][C:9]4[N:8]([CH3:33])[S:7](=[O:34])(=[O:35])[NH:6][C:10]=4[N:11]=3)=[N:16][N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:18]2=[N:19][CH:20]=1
Reactant: COc1ccc(CN2c3nc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)ncc3N(C)S2(=O)=O)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1c2cnc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc2NS1(=O)=O

Procedure:
28 mg (0.050 mmol) of the compound from example 100A were dissolved in 1.5 ml of trifluoroacetic acid and then admixed with 79 μl (0.495 mmol) of triethylsilane, and the mixture was heated to reflux overnight. This was followed by concentration to dryness. After purification by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient), this gave 10.4 mg (48% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13]([N+:21]([O-])=O)=[C:12]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:11]=3)[C:6]=2[CH:31]=1.[H][H]>C(O)C.[Pd]>[NH2:21][C:13]1[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:15][C:10]([N:7]2[C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[N:11][C:12]=1[NH:24][CH:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: [H][H]
Reactant: CCOC(=O)c1nc(-n2cnc3ccc(F)cc32)nc(NC2CCOCC2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1nc(-n2cnc3ccc(F)cc32)nc(NC2CCOCC2)c1N
Reaction time: 10 h
Yield: 76.6 %

Procedure:
Hydrogenation of ethyl 2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-5-nitro-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-carboxylate (310 mg, 0.717 mmol) was performed in ethanol, using Pd/C (10%), under a positive pressure of hydrogen. After 10 h, the catalyst was filtered, washed with portions of methylene chloride, and the combined filtrate concentrated to give the desired amine as a white solid (220 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ, ppm: 8.97 (s, 1H), 8.47 (dd, J=2.6, 2.2 Hz, 1H), 7.74 (m, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.16 (m, 1H), 6.74 (d, J=8.3 Hz, 1H), 4.37-4.32 (m, 3H), 3.94 (d, J=10.4 Hz, 2H), 3.55 (t, J=10.4 Hz, 2H), 2.01 (m, 2H), 1.58 (m, 2H), 1.42 (t, J=7.1 Hz, 3H); LCMS (EI) m/z 401 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14]>[Pd].C(O)C>[NH2:10][C:6]1[CH:5]=[CH:4][C:3]([C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[O:14])=[C:2]([F:1])[C:7]=1[O:8][CH3:9]
Reactant: COc1c([N+](=O)[O-])ccc(C(=O)N2CCOCC2)c1F
Agent: [Pd]
Solvent: CCO
Product: COc1c(N)ccc(C(=O)N2CCOCC2)c1F
Reaction time: 18 h

Procedure:
A suspension of (2-fluoro-3-methoxy-4-nitrophenyl)(morpholino)methanone (0.20 g) and palladium on carbon (0.1 g, 10 wt %) in ethanol was stirred under hydrogen for 18 hours. The reaction then filtered through celite and concentrated to give (4-amino-2-fluoro-3-methoxyphenyl)(morpholino)methanone.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:20][CH3:21])=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH3:31])[CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH3:19][O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:20][CH3:21])[N:3]=[C:2]([NH:30][CH:27]1[CH2:28][CH2:29][CH:24]([N:23]([CH3:31])[CH3:22])[CH2:25][CH2:26]1)[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: COc1cc2nc(Cl)c(-c3ccccn3)nc2cc1OC
Reactant: CN(C)C1CCC(N)CC1
Solvent: Cc1ccccc1
Product: COc1cc2nc(NC3CCC(N(C)C)CC3)c(-c3ccccn3)nc2cc1OC
Yield: 74.9 %

Procedure:
A solution of 2-chloro-6,7-dimethoxy-3-pyridin-2-yl-quinoxaline (0.91 g) and N,N-dimethyl-cyclohexane-1,4-diamine (0.86 g) in toluene (30 mL) was refluxed under nitrogen atmosphere for 16 hours. The reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give a yellow solid. This solid was recrystallized in ethyl acetate/hexane to give the product as yellow crystals (0.92 g); mp 168-171° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][NH:13][C:14](=[O:28])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[O:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:9][CH:8]=2)OCC[O:3]1>Cl.C(Cl)Cl>[C:2]([C:7]1[S:11][C:10]([CH2:12][NH:13][C:14](=[O:28])[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=2[O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:1]
Reactant: CC1(c2ccc(CNC(=O)c3cccnc3Oc3cccnc3)s2)OCCO1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1ccc(CNC(=O)c2cccnc2Oc2cccnc2)s1

Procedure:
A solution of N-[5-(2-Methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2-(pyridin-3-yloxy)-nicotinamide (0.680 g) in 2 N hydrochloric acid (20 ml) and methylene chloride (20 ml) was stirred at room temperature over night. The mixture was extracted with chloroform, washed with water, dried over MgSO4, filtered and concentrated to give a solid which was triturated in diethyl ether to give a white solid. (0.480 g). M.P. 201-203° C.; Anal. calcd. for C18H15N3O3S: C, 61.18; H, 4.28; N, 11.89. Found: C, 60.09; H, 4.25; N, 11.61.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([OH:39])([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:20]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[CH:8]=2)[N:3]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([CH:33]3[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[OH:39])[CH:8]=2)[N:3]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(O)(c2cccnc2)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)C1
Solvent: O=C(O)C(F)(F)F
Product: OC(c1cccnc1)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)C1CCCNC1

Procedure:
tert-Butyl 3-((2,4-dichloro-3-phenylquinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidine-1-carboxylate (88 mg, 0.11 mmol, Example 5) was treated with TFA (0.8 mL) at room temperature for 1 hour and concentrated to give the title compound. 1H NMR (400 MHz, MeOH-d4) δ 9.05 (s, 1H), 8.56-8.72 (m, 3H), 8.02-8.09 (m, 2H), 7.91 (dd, J=5.56, 8.08 Hz, 1H), 7.49-7.58 (m, 2H), 7.29-7.37 (m, 2H), 7.10-7.22 (m, 1H), 3.37-3.46 (m, 1H), 3.27-3.34 (m, 1H), 3.11 (d, J=11.12 Hz, 1H), 3.01 (d, J=12.13 Hz, 1H), 2.84-2.98 (m, 1H), 1.96-2.08 (m, 1H), 1.78-1.96 (m, 1H), 1.64-1.74 (m, 2H); MS m/e 464.4 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]2[C:26]3[C:17](=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:28])([CH3:27])[CH:20]=[C:19]4[CH3:29])[C:16](=[O:30])[O:15][C:11]=2[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.O.CC#N>C1(C)C=CC=CC=1.CCCCCCC.CCOC(C)=O.CCCCCCC>[Si:1]([O:8][C:9]1[C:10]2[C:26]3[C:17](=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:28])([CH3:27])[CH:20]=[C:19]4[CH3:29])[CH:16]([OH:30])[O:15][C:11]=2[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1cccc(O[Si](C)(C)C(C)(C)C)c13
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCCC
Solvent: CC#N
Solvent: O
Product: CC1=CC(C)(C)Nc2ccc3c(c21)C(O)Oc1cccc(O[Si](C)(C)C(C)(C)C)c1-3
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 110.5 %

Procedure:
The product from Example 1 (37.1 g) in toluene (1.8L) under N2 in a 3L 3-necked flask equipped with an overhead mechanical stirrer, addition funnel, and temperature probe was treated with diisobutylaluminum hydride in heptane (132 mL) dropwise at −78° C. over 40 minutes. After complete addition, the reaction mixture was stirred at −78° C. and monitored by HPLC, Zorbax Rx-C8 4.6 mm×25 cm column; mobile phase 90% H2O (0.1% H3PO4):10% CH3CN (0.1% H3PO4) to 30:70 over 15 minutes, then to 10:90 over 20 minutes before ramping back to 10:90 over 2 minutes; 45 minute run; flow rate of 1 mL/minute; UV detection at 225 nm. Retention times: starting material—29.9 minutes; product—20.4 minutes, and/or TLC, EtOAc:heptane (2:3), until starting material was consumed, about 1 hour. Ethyl acetate (500 mL) was added to quench any excess DIBAL, cooling was removed and saturated Rochelle's salt solution (1L) was added. The quenched mixture warmed to room temperature with stirring. The stirring was continued until layers clearly separated. The organic layer was washed with brine (500 mL) before concentrating to a solid. The isolated solid was dried at 40° C. in a vacuum oven to yield 41.2 g of the title compound as a tan solid which was used in the next step without further purification. A small reference sample was crystallized from CH3CN. Anal. calcd for C25H33NO3Si: C, 70.88; H, 7.85; N, 3.31. Found: C, 70.60; H, 7.84; N, 3.22; 1H NMR [(CD3)2SO] δ0.10 (3H, s), 0.97 (9H, s), 1.08 (3H, s), 1.26 (3H, s), 2.24 (3H, s), 5.41 (1H, br), 6.07 (1H, br),6.55˜6.61 (4H, m), 6.91(1H, d), 6.98 (1H, t), 7.99 (1H, d); 13C NMR [(CD3)2SO] δ−4.5, −4.2, 18.0,22.8, 25.8, 25.8, 28.2, 30.1, 49.7, 89.9, 111.2, 113.5, 113.7, 115.7, 116.4, 116.9, 126.2, 127.2, 128.2, 130.2, 132.4, 145.3, 151.0, 151.8 with 2 peaks overlapping; HRMS-FAB: calcd m/z 423.2230, found 423.2232.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[N:21]=[CH:22][N:23]=[CH:24][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[CH:24]=[N:23][CH:22]=[N:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cncnc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ncncc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:29][CH2:30][CH2:31][CH2:32][OH:33])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: NCCCO
Product: Cc1cc(F)ccc1N1CCc2c(NCCCO)nc3c(OCC(F)(F)F)cccc3c21

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.4 mmol) was dissolved in 3-amino-1-propanol(5.0 ml). The reaction mixture was reacted at the same condition of Step 3 in the Example 42 to obtain 520 mg of desired compound as solid in 84% of yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](Cl)=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([O:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:9]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Oc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 951.1 %

Procedure:
A solution of 80 g of 3-chlorophenyl-carboxylic acid chloride in 100 ml of anhydrous benzene was added dropwise with stirring at 10° C. to a mixture of 5.87 g of 4-chlorophenol, 46.1 g of triethylamine and 250 ml of anhydrous benzene and the mixture was stirred overnight at room temperature. The mixture was vacuum filtered and the filtrate was evaporated to dryness to obtain 122 g of raw product which was crystallized from 200 ml of a 2-8 ethyl ether-petroleum ether (b.p.=60°-80° C.) mixture to obtain 116 g of 4-chlorophenyl 3-chlorobenzoate melting at 72° C.
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([CH2:25][C:26]#[N:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.[C:31](#N)[CH3:32].C(N(CC)CC)C.C(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(=O)(O)[O-].CCOC(C)=O>[CH2:31]([N:22]1[CH2:21][CH2:20][C:19]([CH2:25][C:26]#[N:27])([N:17]2[CH:18]=[C:14]([C:12]3[N:11]4[CH:28]=[CH:29][N:30]=[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)[CH2:24][CH2:23]1)[CH3:32]
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCNCC4)c3)n2)cn1
Reactant: CC#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN1CCC(CC#N)(n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)CC1
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
2-(4-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-4-yl)acetonitrile hydrochloride (Example 28, Step A; 27.0 mg, 0.0543 mmol) was suspended in acetonitrile (543 μL, 0.0543 mmol). To this was added triethylamine (30.3 μL, 0.217 mmol) to freebase, followed by acetaldehyde (30.5 μL, 0.543 mmol). After 30 minutes, NaBH(OAc)3 (57.6 mg, 0.272 mmol) was added to reduce. After stirring for 30 minutes, the reaction mixture was diluted in saturated bicarbonate and EtOAc. The aqueous layer was back-extracted with DCM. The combined organic layer was washed with brine, dried with MgSO4, filtered and concentrated. Purification of the resulting crude material by reverse phase HPLC using a 0-100% acetonitrile/water gradient afforded afford 2-(1-ethyl-4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-4-yl)acetonitrile (5.9 mg, 26% yield). MS (apci) m/z=416.2 (M+H).