Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)ccnc2c1C
Product: COc1ccc2c(Cl)ccnc2c1C
Temperature: 25 °C
Yield: 92.6 %

Procedure:
A solution of 4-hydroxy-7-methoxy-8-methylquinoline (59, 6.4 g, 33.8 mmol) in POCl3 (17.2 g, 111.6 mmol) was heated at reflux for 1 h under nitrogen. Then, the resulting solution was cooled down to room temperature and the excess of POCl3 was evaporated under reduced pressure. The residue was partitioned between ice-cold 1N NaOH and AcOEt. The organic layer was dried (Na2SO4), and evaporated. The residue was purified by silica-gel filtration (AcOEt/CH2Cl2/Heptane, 4:4:2) to give 6.5 g (92.5%) of the target product 60 as yellow needles: m/z=208 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH:32]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(C)=NC=2C2C=CC(Cl)=CC=2Cl)CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])[C:11]([CH3:30])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:32][CH2:16]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[6-cyclopropyl-5-(2,4-dichlorophenyl)-3-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.75-1.13, 1.53-1.59, 2.31, 2.98-3.09, 3.35-3.40, 3.57-3.65, 4.23-4.25, 5.37, 5.62, 7.12-7.42; MS (ESI+) for C25H25Cl2N3O m/z 454 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:5]2.[H-].[Na+].I[CH3:23]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([N:12]([CH3:23])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:5]2
Reactant: CC(C)(C)OC(=O)Nc1cc2cc(Br)ccc2cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc2cc(Br)ccc2cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
tert-Butyl 6-bromoisoquinolin-3-ylcarbamate (48 g, 1.5 mmol) was taken up in 10 mL of DMF and chilled to 0° C. Sodium hydride (0.074 g, 1.9 mmol) was added, and the mixture was stirred for 15 minutes. Iodomethane (0.10 mL, 1.6 mmol) was then added, and the mixture was stirred for 30 minutes. The reaction mixture was then quenched with 5 mL of aq NH4Cl. The mixture was then diluted with 50 mL of EtOAc and transferred to a separatory funnel. The mixture was washed five times with 25 mL of water and once with 25 mL of brine. The remaining portion was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0.5% to 7.5% EtOAc/hexanes), affording tert-butyl 6-bromoisoquinolin-3-yl(methyl)carbamate (0.39 g, 78% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.04 (s, 1H) 7.95 (s, 1H) 7.88 (s, 1H) 7.77 (d, J=8.80 Hz, 1H) 7.56 (dd, J=8.61, 1.76 Hz, 1H) 3.48 (s, 3H) 1.57-1.52 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27]([OH:29])=O)[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.N.C[N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27]([NH2:32])=[O:29])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CO[C@H]1CC[C@H](Oc2ncccc2Nc2ncnc3sc(C(=O)O)c(C)c23)CC1
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](Oc2ncccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CC1

Procedure:
Prepared analogously to 1.4 from 0.005 g 4-[2-(trans-4-methoxy-cyclohexyloxy)pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (0.5 M in THF) in DMF using TBTU instead of HATU.
Reaction SMILES: [C:1]1([CH:7]2[CH2:19][C:18](=O)[C:17]3[C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[NH:10][C:9]=3[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:18]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[NH:10][C:9]=2[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19]1)[C:21]([NH2:23])=[NH:22]
Reactant: O=C1CC(c2ccccc2)Cc2[nH]c3c(c21)CCCC3
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2[nH]c3c(c21)CCCC3
Yield: 49.1 %

Procedure:
A mixture of 2-phenyl-1,2,3,4,5,6,7,8-octahydrocarbazol-4-one (0.8 g), aminoguanidine hydrochloride (0.35 g), concentrated hydrochloric acid (0.15 ml), water (0.15 ml) and ethanol (50 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution. The solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (EtOAc/MeOH) and dissolved in ethanol. To the solution was added 1N hydrochloric acid (4 ml), and the solvent was evaporated. The residue was recrystallized from ethanol to give 4-guanidinoimino-2-phenyl-1,2,3,4,5,6,7,8-octahydrocarbazole hydrochloride (Compound 5) (0.53 g) as amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1F)[C:27]#[N:28]>CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:23])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-n2ccc(OCc3ccccc3)cc2=O)c(F)c1
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To 4-(benzyloxy)pyridin-2(1H)-one (0.358 g, 1.779 mmol) under nitrogen was added DMF (5 mL) to produce a tan suspension. To the reaction was added NaH (60% in oil) (0.074 g, 1.860 mmol) and stirred for 1.5 hours and then 3,4-difluorobenzonitrile (0.225 g, 1.618 mmol) was added. The reaction was placed in a 90° C. oil bath for 2 hours. To the tan suspension was added 50 mL of EtOAc and the mixture washed with 4×25 mL of water, dried over MgSO4, filtered and concentrated to give 0.42 g pale yellow solids. This material was purified by flash chromatography (1-5% MeOH in CH2Cl2) to yield product (263 mg, 0.805 mmol, 50%) as a tan solid. MS (ESI) 321.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:24][O:25][CH:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH2:28][CH2:27][CH:26]([O:25][CH3:24])[CH3:30])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: COC(C)CCN
Product: COC(C)CCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxybutan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (d, J=6.32 Hz, 3H) 1.52-1.70 (m, 2H) 3.17 (s, 3H) 3.26-3.36 (m, 3H) 7.72 (d, J=8.59 Hz, 2H) 8.07 (d, J=6.57 Hz, 2H) 8.27-8.50 (m, 2H) 8.61 (t, J=5.43 Hz, 2H) 8.76-8.96 (m, 1H) 13.46 (br. s., 1H). MS m/z [M+H]+ 392.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([O:15]CC)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[ClH:18]>O1CCOCC1>[ClH:18].[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCN(c2ccncc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C1CCN(c2ccncc2)CC1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
2.95 g (12.6 mmol) of ethyl 1-(4-pyridyl)-piperidine-4-carboxylate was stirred in 100 ml of dioxane. After adding 50 ml of 1 N hydrochloric acid, the obtained mixture was stirred at 95° C. for 20 hours. The solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:23][C:24](=[O:50])[CH:25]([N:29]([C:31](=[O:49])[CH:32]([NH:41]C(OCCCC)=O)[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:14](=[O:22])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:23][C:24](=[O:50])[CH:25]([N:29]([C:31](=[O:49])[CH:32]([NH2:41])[CH2:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:14](=[O:22])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCOC(=O)NC(Cc1ccc(F)cc1)C(=O)N(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C(=O)Nc1ccccn1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C(=O)Nc1ccccn1)N(C)C(=O)C(N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.9 %

Procedure:
To a solution of 2-((2-butoxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(2-pyridylcarbamoyl)ethylamide (1.67 g, 2.41 mmol) in methylene chloride (30 ml), TFA (5 ml) was added and stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure; the thus obtained residue was mixed with chloroform, washed with a saturated aqueous NaHCO3 solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: methanol:aqueous ammonia:methylene chloride=3:0.1:100), giving the titled compound (370 mg).
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])=[O:24])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:35]=[CH:34][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[S:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:32])[CH3:33])[C:27]([OH:29])=[O:28])=[O:24])=[N:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)s1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)s1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(5-(4-(4-tert-butylbenzamido)phenyl)thiazole-2-carboxamido)-3-methylbutanoate (110 mg) in THF (2.2 ml) was added 1 M aqueous solution of Lithium hydroxide monohydrate (0.44 ml) and the reaction mixture was stirred at RT for 4 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, concentrated under vacuum to get off white solid which was crystallized in EtOAc to give the title compound. Yield: 87 mg (81%); 1H NMR (DMSO-d6, 300 MHz): δ 13.02 (bs, 1H), 10.38 (s, 1H), 8.4 (s, 1H), 8.36 (d, 1H), 7.94 (d, 2H), 7.91 (d, 2H), 7.8 (d, 2H), 7.58 (d, 2H), 4.32 (m, 1H), 2.26 (m, 1H), 0.95 (d, 6H); MS (ES+) m/z 480 (M+1).
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]([CH2:8][CH3:9])[C:5](Cl)=[O:6])#[N:2].[CH3:22][NH:23][CH3:24]>C(Cl)Cl>[C:1]([C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]([CH2:8][CH3:9])[C:5]([N:23]([CH3:24])[CH3:22])=[O:6])#[N:2]
Reactant: CNC
Reactant: CCC(C(=O)Cl)C(C#N)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCC(C(=O)N(C)C)C(C#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-cyano-3,3-diphenyl-2-ethylpropionyl chloride (0.1 mol prepared from 0.1 mol of the acid as described above) in 100 ml of methylen chloride was added dropwise while stirring to a mixture of 65 ml of 33% aqueous dimethylamine (ca. 0.5 mol) and 100 g of crushed ice. The mixture was stirred for 1 hour at room temperature, whereupon the organic phase was separated and washed with dilute hydrochloric acid. After drying over magnesium sulphate, filtration and evaporation, the residue was crystallized from a mixture of methylene chloride and ether. Yield: 28 g (88%) of the amide as a white crystalline substance melting at 170°-172° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([CH2:23][O:24][CH3:25])=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.N1C=CC=CC=1.[C:32](Cl)([CH3:34])=[O:33].[OH-].[Na+]>C1COCC1>[CH3:25][O:24][CH2:23][C:7]1[C:6]2[C:2]([NH:1][C:32](=[O:33])[CH3:34])=[N:3][NH:4][C:5]=2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[N:8]=1
Reactant: CC(=O)Cl
Reactant: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(NC(C)=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-1-(3-amino-4-(methoxymethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (30 mg, 0.088 mmol) in THF (1 ml) was charged with pyridine (72 μl, 0.890 mmol) and AcCl (62 μl, 0.872 mmol). The mixture was stirred at RT for 17 hr before 1N NaOH (1.2 ml, 1.200 mmol) was added and stirred at RT for 2 hr and then heated to 50° C. for 1 hr. The reaction was quenched with sat aq NH4Cl and extracted into EtOAc. The mixture was washed with sat aq NH4Cl followed by brine, dried over MgSO4, filtered, concentrated in vacuo and purified via flash chromatography (0-20% MeOH/DCM) to give (R)—N-(4-(methoxymethyl)-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd for C19H23N6O3 [M+H]+ 383. found 383. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.01 (s, 1H), 9.13 (s, 1H), 7.33 (m, 5H), 7.22 (m, 1H), 4.89 (t, J=6.8 Hz), 4.59 (s, 2H), 3.28 (s, 3H), 2.06 (s, 3H), 1.39 (d, 5.1 Hz).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=2)[C:25]=1[O:26][CH3:27])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=2)[C:25]=1[O:26][CH3:27])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1c(-c2ccnn2C)csc1C(=O)NC(Cc1ccccc1)CN(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(-c2ccnn2C)csc1C(=O)NC(CN)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[2-({[3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part b) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated with a toluene azeotrope and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: C([Li:5])CCC.CCCCCC.[CH3:12][Si:13]([CH3:20])([CH3:19])[NH:14][Si:15]([CH3:18])([CH3:17])[CH3:16]>>[CH3:12][Si:13]([CH3:20])([CH3:19])[N-:14][Si:15]([CH3:18])([CH3:17])[CH3:16].[Li+:5]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCCCCC
Product: C[Si](C)(C)[N-][Si](C)(C)C
Product: [Li+]

Procedure:
A solution of n-butyllithium in hexane (1.55M, 390 ml, 0.605 moles) is cooled to 0° C. and treated dropwise over a period of 15 min with neat hexamethyldisilazane (118.12 g, 0.7337 moles). The resulting yellow solution is then refluxed for 1.5 hr, and concentrated in vacuo to yield a white solid residue. To remove the excess hexamethyldisilazane, this residue is dissolved in heptane, and the heptane is removed in vacuo. The material is then tumble-dried (50° C./2 mm/30 min). The final product is a white solid with a melting point of 70°-83° C.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH2:13]([N:15]([CH2:18][CH2:19]Cl)[CH2:16][CH3:17])[CH3:14]>>[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH2:17][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: Sc1ncnc2ccccc12
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCSc1ncnc2ccccc12
Yield: 59.9 %

Procedure:
The title compound(4.82 g) was prepared from 4-mercaptoquinazoline(5.0 g) and N,N-diethylaminoethylchloride hydrochloride(5.3 g).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[OH:31][C:32]1[C:33]([C:38]([NH:40][NH2:41])=O)=[N:34][CH:35]=[CH:36][CH:37]=1>ClCCl>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:38]([C:33]3[C:32]([OH:31])=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:40][N:41]=[C:26]2[CH2:25]1)=[O:23]
Reactant: NNC(=O)c1ncccc1O
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2ncccc2O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethyloxonium tetrafluoroborate (341 mg, 1.795 mmol) was added under argon to a solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (475 mg, 1.632 mmol) in dry Dichloromethane (DCM) (4 mL). The mixture was stirred at room temperature for 1 hour 15 min—the solution was clear. 3-hydroxy-2-pyridinecarbohydrazide (I93) (300 mg, 1.958 mmol) was added under argon. The reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the remaining residue was dissolved in 1-butanol (4.00 mL). The mixture was stirred at reflux 1 day. The solvent was evaporated under reduced pressure. The remaining residue was dissolved into ethyl acetate (75 mL), extracted with water (3×10 mL) and with brine (2×10 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by MDAP. The resulting solid was triturated in diethyl ether (15 mL) and dried under vacuum at 50° C. for 3 days to afford the desired product in 9.0 mg as a pinkish powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.Br[C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1.C(OCC)C.CCCCCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1)=[O:6]
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Reactant: Brc1cncnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(c1cncnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
61.8 g (0.3 mole) of methyl 2,4-dichlorobenzoate and 52.2 g (0.33 mole) of 5-bromopyrimidine are dissolved in a mixture of 400 ml of tetrahydrofuran and 200 ml of diethyl ether. After the addition of 30 g of molecular sieve, the reaction mixture is stirred for 1/2 hour at room temperature and then cooled to about -120° C. 187.2 ml (0.3 mole) of butyl lithium as a 1.6 molar solution in hexane are added dropwise at this temperature. The reaction mixture is then stirred for 11/2 hours in the temperature range from -100° to -130° C. Subsequently, while allowing the temperature to increase to room temperature, stirring is continued until the reaction is complete. 300 ml of 10% ammonium chloride solution are then added dropwise, and the reaction mixture is extracted three times with ethyl acetate. The organic solution is dried over sodium sulfate and then filtered, and the filtrate is concentrated. The resultant crude product is then purified through a flash column packed with silica gel (eluant: a 3:1 mixture of petroleum ether and ethyl acetate), affording 45 g (59.3% of theory) of the title compound with a melting point of 75°-78° C.
Reaction SMILES: ClC1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][NH:13][CH3:14])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH2:48]([Cl:50])Cl>>[Cl:50][C:48]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][N:13]([CH3:14])[C:30](=[O:32])[N:15]([CH:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]4)[C:5]=3[C:4]=2[N:3]=1
Reactant: CNCc1cnc2ccc(Cl)nc2c1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: CN1Cc2cnc3ccc(Cl)nc3c2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DCM (10 mL) was dissolved tert-butyl 4-((6-chloro-3-((methylamino)methyl)-1,5-naphthyridin-4-yl)amino)piperidine-1-carboxylate (0.312 g, 0.77 mmol). The solution was cooled in an ice bath, and triphosgene (0.274 g, 0.923 mmol) and triethylamine (0.324 mL) were added. Then the reaction mixture was stirred at ambient temperature for 2 h. The reaction was quenched with saturated aqueous sodium carbonate and extracted with DCM. The organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure to give a solid (0.332 g), which was used in the subsequent procedure without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:26](Cl)(Cl)=[O:27].C1(C)C=CC=CC=1.[NH2:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([S:13][C:26]([NH:37][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[O:27])=[CH:9][C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S)cc1-c1ccccc1
Reactant: Nc1nccs1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(SC(=O)Nc2nccs2)cc1-c1ccccc1

Procedure:
To a solution of 2-phenyl4-mercaptobenzoyl-methionine methyl ester from example 12E or 12F (1 equivalent) in methylene chloride is added a solution of phosgene in toluene (1.0 equivalent) and p-dimethylaminopyridine (2.0 equivalents). When the reaction is judged complete by TLC analysis, the solvent is evaporated with toluene chasers. The thiochloroformate is reacted without further purification with 2-aminothiazol (1.0 equivalent) and triethylamnine (1.0 equivalent) in dichloromethane. When judged complete by TLC analysis, the reaction is taken up in ethyl acetate and washed with 1N HCl and brine, evaporated, and purified by chromatography on silica gel.