Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([NH:12][C:13](=[O:23])[C@@H:14]([NH2:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=[CH:10][CH:11]=2)=[N:2]1.[S:24]1[CH:28]=[C:27]([CH:29]=O)[N:26]=[CH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([NH:12][C:13](=[O:23])[C@@H:14]([NH:22][CH2:29][C:27]3[N:26]=[CH:25][S:24][CH:28]=3)[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:9]=[CH:10][CH:11]=2)=[N:2]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2cc[nH]n2)c1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2cc[nH]n2)c1)[C@H](Cc1ccccc1)NCc1cscn1
Reaction time: 1 h
Yield: 25.4 %

Procedure:
To a solution of (2S)—N-(3-(1H-pyrazol-3-yl)phenyl)-2-amino-3-phenylpropanamide 12.C (200 mg, 0.65 mmol) in DCM (5 mL) was added thiazole-4-carbaldehyde (73 mg, 0.65 mmol, available from Combi-Blocks). The mixture was stirred for 1 h, then sodium triacetoxyborohydride (207 mg, 0.98 mmol) was added and the mixture stirred for an additional hour at room temperature. The mixture was then concentrated and the crude product purified by reverse phase chromatography (0-100% CH3CN/water+0.5% TFA) to afford (2S)—N-(3-(1H-pyrazol-3-yl)phenyl)-3-phenyl-2-(thiazol-4-ylmethylamino)propanamide 12 as a white solid (66.7 mg, 25% yield). LCMS ESI (pos.) m/e: 404.0 (M+1): 1H NMR (500 MHz, MeOH-D4) δ ppm 9.11 (d, J=1.96 Hz, 1H), 7.82-7.87 (m, 1H), 7.80 (d, J=1.96 Hz, 1H), 7.74 (d, J=2.20 Hz, 1H), 7.51-7.60 (m, 1H), 7.21-7.38 (m, 7H), 6.68 (d, J=2.20 Hz, 1H), 4.50 (d, J=5.38 Hz, 2H), 4.29 (dd, J=9.29, 5.87 Hz, 1H), 3.43 (dd, J=13.45, 5.62 Hz, 1H), 3.27 (dd, J=13.45, 9.29 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[C:25]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>O=S(Cl)Cl>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:15][CH:14]=2)=[CH:34][CH:35]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 1A (570 mg, 2.86 mmol) in SOCl2 (10 mL) was refluxed for 1 hour. The solution was allowed to cool to room temperature and SOCl2 was removed under reduced pressure. The residue was taken up in tetrahydrofuran (10 mL) and treated with DIEA (2.5 mL, 14.4 mmol, 5 eq) and 4-tert-butylaniline (0.41 mL, 2.57 mmol). After stirring overnight at room temperature, the tetrahydrofuran was removed under reduced pressure and replaced with ethyl acetate (20 mL). The ethyl acetate was washed with H2O and brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel (eluant gradient from 7:3 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.71-8.74 (m, 1H), 8.23-8.26 (m, 2H), 8.07-8.10 (m, 3H), 7.94 (td, J=7.4 Hz, 2.1 Hz, 1H), 7.70-7.73 (m, 2H), 7.37-7.44 (m, 3H), 1.29 (s, 9H); MS (ESI+) m/z 331 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]1[S:15][N:14]=[C:13]2[CH:16]=[C:17]([CH:20]=O)[CH:18]=[CH:19][C:12]=12.C([O:24][C:25](=O)[C:26](=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=1)C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:20]([C:17]4[CH:18]=[CH:19][C:12]5=[N:11][S:15][N:14]=[C:13]5[CH:16]=4)[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=4)=[C:26]([OH:35])[C:25]3=[O:24])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccc2nsnc2c1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CCOC(=O)C(=O)Cc1cccc(O)c1
Solvent: CCO
Product: O=C1C(O)=C(c2cccc(O)c2)C(c2ccc3nsnc3c2)N1c1ccc2[nH]cnc2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and Benzo[1,2,5]thiadiazole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3-(3-Hydroxy-phenyl)-2-oxo-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].Cl.[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])[CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCN(C(C)C)C(C)C.CN(C=O)C>[CH2:1]([NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])[CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)C1CCC(CN)CC1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)CNCC1CCC(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isobutyraldehyde (0.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydro-chloride from Example E10.2 (1.88 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=396.4
Reaction SMILES: [C:1](O)(=O)[CH:2]=[CH2:3].[C:6](O)(=O)[CH:7]=[CH2:8].[C:11](O)(=O)[CH:12]=C.[CH2:16]([C:18](CO)([CH2:21]O)[CH2:19][CH3:20])O.C(OCC(COC(=O)C=C)(COC(=O)C=C)COC(=O)C=C)(=O)C=C>>[CH2:3]=[CH:2][C:1]1[CH:12]=[CH:11][CH:6]=[CH:7][CH:8]=1.[CH2:20]=[CH:19][C:18](=[CH2:16])[CH3:21]
Reactant: C=CC(=O)O
Reactant: CCC(CO)(CO)CO
Agent: C=CC(=O)OCC(COC(=O)C=C)(COC(=O)C=C)COC(=O)C=C
Product: C=CC(=C)C
Product: C=Cc1ccccc1

Procedure:
The method of Example IV was repeated except that 11.3 m moles of initiator were added in each of the two polymerization steps and 135.6 m moles of trimethylolpropane triacrylate was added instead of the pentaerythritol tetraacrylate. Again, a copolymer of 15% by weight of styrene and 85% by weight isoprene was prepared.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C@H:4]1[O:14]CC1C=CC=CC=1.[H][H]>[Pd].CO>[OH:14][C@H:4]1[C@@H:3]([NH:2][CH3:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1
Reactant: [H][H]
Reactant: CCOC(=O)N1CC[C@H](NC)[C@H](OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CC[C@H](NC)[C@H](O)C1
Yield: 95 %

Procedure:
A mixture of 150 parts of cis-ethyl 4-(methylamino)-3-(phenylmethoxy)-1-piperidinecarboxylate and 560 parts of methanol was hydrogenated at normal pressure and at 50° C. with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 101 parts (95%) of ethyl cis-3-hydroxy-4-(methylamino)-1-piperidinecarboxylate (10).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C-:16]#[N:17].[K+].C(=O)(O)[O-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:16]#[N:17])=[C:4]([I:14])[C:5]=1[O:11][CH2:12][CH3:13])(=[O:10])[CH3:9]
Reactant: [C-]#N
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1I
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1I
Temperature: 40 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (7.3 g, 21 mmol) in N,N-dimethylformamide (80 mL)was treated with potassium cyanide (2.1 g, 32 mmol) and stirred at 40° C. for 5 h. The reaction mixture was diluted with ethyl acetate and poured into saturated sodium bicarbonate solution/water (1:1). The organic layer was separated, washed with saturated sodium bicarbonate solution, dried with magnesium sulfate, filtered, and concentrated to give a crude brown oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-30%) to give the desired product (6.1 g, 81%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 3.93 (q, J=7.0 Hz, 2H), 2.61 (s, 3H), 1.47 (t, J=7.0 Hz, 3H). LCMS for C11H10ClINO2 (M+H)+: m/z=349.9; Found: 349.9.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23]C(O[CH2:27][CH2:28]OC)=O>>[ClH:23].[C:2]1([CH2:1][N:8]2[CH2:9][CH2:10][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:12][CH2:13]2)[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:28]=2[CH:27]=1
Reactant: COCCOC(=O)Cl
Reactant: COCCOC(=O)N(C)C1CCN(Cc2ccccc2)CC1
Product: COCCOC(=O)N(C)C1CCN(CC2=Cc3ccccc32)CC1
Product: Cl

Procedure:
This compound was prepared in accordance with the process described in Example 11 (Stages B and C) but using 2-methoxyethyl N-(1-benzylpiperid-4-yl)-N-methylcarbamate in Stage B. The latter is obtained in accordance with the process described in Stage B of Example 1 using methoxyethyl chloroformate instead of propionyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[O:9])[C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Product: Cc1ccc(-c2cnccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using 5-methyl-2-(pyrazin-2-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]3[N:39]=[CH:40][N:41]=[C:15]23)[CH2:10][CH2:9]1)[C:2]1C=CC=CC=1.O1CCCC1>[C].[Pd].C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]3[N:39]=[CH:40][N:41]=[C:15]23)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(Cc3ccccc3)CC2)c2ncnn12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-{[4-(1-benzylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (4.82 g), 10% palladium-carbon (2.39 g), tetrahydrofuran (30 mL) and ethanol (60 mL) was stirred at room temperature for 2 days under a hydrogen atmosphere. The reaction mixture was filtered, and the solvent was evaporated. The residue was purified by basic silica gel chromatography [eluent: methanol/ethyl acetate=0/10→05/95 (volume ratio)] to give the title compound as a colorless amorphous compound (146 mg, 3%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:42]=[C:43]([Cl:45])[CH:44]=1)[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:33]([CH3:36])=[N:34][N:35]=3)[C:27]=2[CH:26]=[C:25]1[C:37]1[NH:41][N:40]=[CH:39][CH:38]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:48]I>CN(C=O)C>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:42]=[C:43]([Cl:45])[CH:44]=1)[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:33]([CH3:36])=[N:34][N:35]=3)[C:27]=2[CH:26]=[C:25]1[C:37]1[CH:38]=[CH:39][N:40]([CH3:48])[N:41]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cc(Cl)cc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)n12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4ccn(C)n4)n3Cc3cc(Cl)cc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)n12
Reaction time: 0.17 h

Procedure:
6-[3-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.20 g, 0.22 mmol, from Step 4) in DMF (4.7 mL) was treated with NaH (60% in mineral oil, 27 mg, 0.66 mmol). After 10 minutes, MeI (41 μL, 0.66 mmol, Aldrich) was added to the reaction mixture. After 10 minutes, the reaction was quenched by the addition of water, and the product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (50 mg, 30%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH3:15])=[C:10]([CH:12](O)[CH3:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[ClH:18].[C:1]1([C:7]2[NH:8][C:9]([CH3:15])=[C:10]([CH:12]([Cl:18])[CH3:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(C)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(-c2ccccc2)nc1C(C)Cl
Product: Cl

Procedure:
27 Grams (0.13 mol) of 2-phenyl-4-(1-hydroxyethyl)-5-methylimidazole were dissolved in 700 ml of chloroform with 44 ml (0.6 mol) of thionyl chloride and refluxed for 5 hours. After cooling, the mixture was evaporated, the residue triturated in acetone, thereby giving, in approximately stoichiometric yield, 2-phenyl-4-(1-chloroethyl)-5-methylimidazole hydrochloride, m.p. 190° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([OH:18])[CH2:13]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([OH:18])[CH2:13]2)[N:7]=1.[Cl:1][C:2]1[N:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([OH:18])[CH2:13]2)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1
Reactant: N[C@H]1CCC[C@@H](O)C1
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(Cl)nc1N[C@@H]1CCC[C@H](O)C1
Product: N#Cc1cnc(N[C@@H]2CCC[C@H](O)C2)nc1Cl
Temperature: -60 °C
Reaction time: 1 h
Yield: 20 %
Yield: 46 %

Procedure:
2,4-Dichloropyrimidine-5-carbonitrile (900 mg, 5.17 mmol) in anhydrous ethanol (5 mL) and (1R,3S)-3-amino-cyclohexanol (624 mg, 5.43 mmol; prepared as described in Tetrahedron: Asymmetry 15 (2004) 2051-2056) in anhydrous ethanol (5 mL) were mixed at −60° C. and then DIEA (1.0 g, 7.75 mmol) was added dropwise. The mixture was stirred at −60° C. for 1 h and then at room temperature overnight. Volatile fractions were removed and the residue was purified on silica gel (eluting with 9.1%-33% ethyl acetate in petroleum ether) to give 4-chloro-2-((1R,3S)-3-hydroxycyclohexylamino)-pyrimidine-5-carbonitrile (600 mg, 2.38 mmol, yield 46%) as a white solid and 2-chloro-4-((1R,3S)-3-hydroxycyclohexylamino)pyrimidine-5-carbonitrile (270 mg, 1.07 mmol, yield 20%; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1H), 8.46 (d, J=7.81 Hz, 1H), 4.83 (d, J=3.90 Hz, 1H), 3.95-4.11 (m, 1H), 3.45-3.61 (m, 1H), 1.93 (d, J=11.71 Hz, 1H), 1.60-1.84 (m, 3H), 1.03-1.50 (m, 4H); MS (ESI) m/z. 253.2 [M+1]+) as a white solid. The regiochemistry of the minor regioisomer was confirmed in step B below.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:14]1([NH:20][C:21](=[S:22])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC(N)=O
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)CNC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
A mixture of glycinamide hydrochloride (8.25 g), triethyl amine (10.0 g), phenyl-isothiocyanate (10.1 g), and methylene chloride (300 mL) was heated at reflux for 1 hour. The mixture was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with methylene chloride, then with diethyl ether and air dried to give 2-(3-phenyl-thioureido)-acetamide (9.7 g), m.p. 150°-152° C. Anal. Calcd. for. C9H11N3O S: C, 51.66; H, 5.30; N, 20.08. Found: C, 51.41; H, 5.04; N, 20.02. Mass spectrum (El, M.+) m/z 209. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.88 (s, 1H), 7.70 (t, 1H), 7.52 (s, 1H), 7.47 (d, 2H), 7.31 (t, 2H), 7.15 (s, 1H), 7.09 (t, 1H), and 4.08 ppm (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([OH:26])=O)[C:13]2=[O:27])=[O:10])[CH:7]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:63][N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CN1C(=O)CCC1.CC#N>[Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([N:67]3[CH2:68][CH2:69][N:64]([CH3:63])[CH2:65][CH2:66]3)=[O:26])[C:13]2=[O:27])[CH:7]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)N3CCN(C)CC3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of {1-[(5-Chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (0.515 g, 1.14 mmol) in NMP (8 ml), triethylamine (0.166 ml, 1.26 mmol) is added followed by HATU (0.452 g, 1.26 mmol). The mixture is stirred at RT for 5 minutes and then treated with 1-methylpiperazine (140.3 μL, 1.26 mmol). After 5 minutes at RT the reaction mixture is partitioned between EtOAc (25 ml) and water (25 ml). The phases are separated and the aqueous phase is washed further with EtOAc (2×20 ml). The organic extracts are combined, washed with saturated NaHCO3 (40 ml), brine (40 ml), dried (MgSO4), filtered and concentrated to give a brown oil. The residue is taken up in MeCN (5 ml) and passed through a 10 g Varian pre packed silica cartridge, eluting with MeCN then EtOAc to remove the impurities. The product is eluted off the column with MeOH. The MeOH fractions are combined and concentrated in vacuo and dried to afford the title compound, [M+H]+ 530.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:23][CH:22]([C:24]([OH:26])=[O:25])[CH2:21]1.C(N(CC)CC)C.Cl>CN(C=O)C.O>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:23][CH:22]([C:24]([OH:26])=[O:25])[CH2:21]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=C(O)C1CNC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(N3CC(C(=O)O)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (2.84 g, 10.5 mmol) and azetidine-3-carboxylic acid (1.06 g, 10.5 mmol) in DMF (100 mL) was added triethylamine (3.18 g, 4.39 mL, 31.5 mmol). The reaction was stirred at room temperature overnight then diluted with H2O (400 mL). The pH of the solution was adjusted to 3-4 by addition of an aqueous 1 M HCl solution. The white precipitate then obtained was filtered, washed with H2O, and purified by silica gel chromatography using 0-15% MeOH—CH2Cl2 giving 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxylic acid. LC/MS: m/z 336.3 (M+H)+ at 1.97 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:6]3[N:7]([C:23]([C:26]#[N:27])=[CH:24][N:25]=3)[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[CH:1]1([NH:4][C:5]2[C:6]3[N:7]([C:23]([C:26]#[N:27])=[CH:24][N:25]=3)[N:8]=[C:9]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:16][CH:17]=3)[CH:10]=2)[CH2:3][CH2:2]1
Reactant: CCN(CC)c1ccc(Nc2cc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN(CC)c1ccc(Nc2cc(NC3CC3)c3ncc(C#N)n3n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.12 %

Procedure:
A solution of 244A (5 mg, 10.38 μmol) in DCM (1 mL) was treated with TFA (1 mL, 12.9 mmol) and stirred at room temperature for three hours. The reaction mixture was concentrated and dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min., 20 min. gradient, monitored at 220 nm) to give Example 244, (1.2 mg, 22.12% yield). HPLC: Rt=3.178 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=362.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.09-11.33 (1H, m), 9.70 (1H, s), 8.15 (1H, s), 7.82-8.05 (2H, m), 7.51-7.67 (2H, m), 6.24 (1H, s), 1.01 (6H, t, J=6.80 Hz), 0.72-0.86 (2H, m, J=5.54 Hz), 0.53-0.72 (2H, m, J=2.77 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]3[C:29]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[CH:19]=[CH:18][C:17]=1[F:36])[C:11](=[O:37])[NH:10]2)=[O:5])[CH3:2].N1C=CC=CC=1.Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46].Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]3[C:29]([O:30][CH2:31][CH2:32][O:33][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[CH:19]=[CH:18][C:17]=1[F:36])[C:11](=[O:37])[NH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1scc2[nH]c(=O)n(-c3cc(OCc4c(OCCO)ccc(F)c4F)ccc3F)c(=O)c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)OCCOc1ccc(F)c(F)c1COc1ccc(F)c(-n2c(=O)[nH]c3csc(C(=O)OCC)c3c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-ethoxycarbonyl-3-{2-fluoro-5-[2,3-difluoro-6-(2-hydroxyethoxy)benzyloxy]phenyl}thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (80 mg) in ethyl acetate (2 mL) were added pyridine (0.036 mL) and ethyl chloroformate (0.021 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give the title compound (38 mg).