Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])=[CH:10][C:11](=[O:21])[C:12]=1[O:13]CC1C=CC=CC=1)=[O:6])([CH3:3])[CH3:2].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:25])=[O:26])=[CH:10][C:11](=[O:21])[C:12]=1[OH:13])=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)NC(C)C)n1C
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(O)c(C(=O)NC(C)C)n1C
Yield: 54 %

Procedure:
3-Hydroxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (18-02) (110.0 mg, 54.01%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-02) (250.0 mg, 0.518 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=3Cl)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:29])[CH:5]=1)(=[O:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=3[N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:29])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(N)(=O)=O)ccc3Cl)CC2)c(F)c1
Reactant: C1COCCN1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(N)(=O)=O)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-chloro-benzenesulfonamide and morpholine (39%, yellow solid), MS (m/e): 489.4 (M−H, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([NH:11][O:12][CH3:13])=[O:10])=[CH:4][C:3]=1[NH:14][C:15]1[C:20]2=[C:21]([CH:27]([CH3:29])[CH3:28])[C:22]([C:24]([OH:26])=O)=[CH:23][N:19]2[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C.C1(P([N:51]=[N+:52]=[N-:53])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9](=[O:10])[NH:11][O:12][CH3:13])=[CH:4][C:3]=1[NH:14][C:15]1[C:20]2=[C:21]([CH:27]([CH3:28])[CH3:29])[C:22]([C:24]([N:51]=[N+:52]=[N-:53])=[O:26])=[CH:23][N:19]2[N:18]=[CH:17][N:16]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CONC(=O)c1cc(Nc2ncnn3cc(C(=O)O)c(C(C)C)c23)c(F)cc1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CONC(=O)c1cc(Nc2ncnn3cc(C(=O)N=[N+]=[N-])c(C(C)C)c23)c(F)cc1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of Example 22 (1.11 g, 2.74 mmol) in dioxane (25 mL) was added triethylamine (0.57 mL, 4.1 mmol) followed by diphenylphosphoryl azide (0.77 mL, 3.57 mmol) and the resulting mixture was stirred at 40° C. After 1 h, the mixture was concentrated and the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to afford acyl azide, 4-(2,4-difluoro-5-methoxycarbamoyl-phenylamino)-5-isopropyl-pyrrolo[2, 1-f][1,2,4]triazine-6-carbonyl azide (0.95 g, 81%) as pale yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([C:24]#[C:25][CH2:26][OH:27])[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1>CO.[Pd]>[F:1][C:2]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][OH:27])[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)NOCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Agent: [Pd]
Solvent: CO
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(CCCO)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-[2-Fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (122 mg, 0.33 mmol) was dissolved in MeOH (20 mL), 5% Pd/C (20 mg) added, then the mixture stirred under an atmosphere of hydrogen (60 psi) for 15 h. at R.T. The Pd/C was removed by filtration through Celite® and all solvent removed under reduced pressure to yield crude yellow oil that was purified by chromatography on silica gel (10% MeOH/CH2Cl2 as eluant). 4-[2-Fluoro-4-(3-hydroxypropyl)anilino]-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was isolated as a pale yellow foam (63%). 1H NMR [(CD3)2SO, 400 MHz] δ 11.60 (v br s, 1H), 9.29 (br s, 1H), 8.13 (s, 1H), 7.33 (t, J=8.3 Hz, 1H), 7.18 (d, J=11.7 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 5.40 (s, 1H), 4.77 (br s, 1H), 4.49 (t, J=5.1 Hz, 1H), 3.91 (t, J=3.9 Hz, 2H), 3.62 (t, J=4.8 Hz, 2H), 3.41 (q, J=5.9 Hz, 2H), 3.36 (s, 3H), 2.62 (t, J=7.6 Hz, 2H), 1.74 (pentet, J=7.0 Hz, 2H). HRMS (EI+) calcd for C18H23N3O5F 380.1622 (M+), found 380.1623.
Reaction SMILES: O=[C:2]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[NH:8][CH:7]=1)[C:3]([NH2:5])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[NH2:5][CH2:3][CH2:2][C:6]1[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][N:11]=2)[NH:8][CH:7]=1
Reactant: NC(=O)C(=O)c1c[nH]c2cccnc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCc1c[nH]c2cccnc12
Temperature: 0 °C

Procedure:
A solution of 2-oxo-2-(1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide (1 eq.) in ether is treated with lithium aluminum hydride (4 eq.), heated at reflux temperature for 8 h, cooled to 0° C., quenched by addition of Rochelle's salt solution and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated to afford the title amine, which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH:19]3[CH2:21][CH2:20]3)[C:9]2=[O:22])[CH:5]=[CH:4][N:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C(C)=CC=CC=1>[CH:19]1([C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:10]2[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH:23]4[CH2:25][CH2:24]4)[CH:7]=3)[C:9]2=[O:22])[CH2:21][CH2:20]1
Reactant: OB(O)C1CC1
Reactant: O=C1N(c2ccnc(Cl)c2)CCN1c1cnccc1C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C1N(c2ccnc(C3CC3)c2)CCN1c1cnccc1C1CC1
Yield: 33.4 %

Procedure:
1-(2-chloropyridin-4-yl)-3-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-39a: 220 mg, 0.7 mmol) was reacted with cyclopropyl boronic acid (72 mg, 0.84 mmol), Pd(PPh3)4 (41 mg, 0.035 mmol), potassium carbonate (194 g, 1.4 mmol) and xylene (10 mL) in seal tube at 125° C. for 14 hours. Purification by column chromatography on silica gel (1% methanol in chloroform) afforded 75 mg of the product (33.48% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:15](OCC)=[O:16])[CH3:2].[NH2-:22].[Li+].C(O)(=O)C.[ClH:28]>CCOCC>[ClH:28].[CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:15]([NH2:22])=[O:16])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(OC)cc2c1N(CC)CC
Reactant: [NH2-]
Agent: Cl
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCN(CC)c1c(C(N)=O)[nH]c2ccc(OC)cc12
Yield: 36 %

Procedure:
Prepared from ethyl 3-(diethylamino)-5-methoxy-1H-indole-2-carboxylate (Unangst PC, et al., J. Heterocyclic Chem. 1987;24:817) and lithium amide by the procedure described in Example 18, with the exception that dilute acetic acid is substituted for 1.0N HCl during the wash of the ethyl acetate extracts. The crude product is purified by flash chromatography (silica gel, 30% ethyl acetate in dichloromethane elution) to give a foam. The foam is dissolved in ether and treated with gaseous HCl to provide the product salt in 36% yield after recrystallization from acetonitrile; mp 244° C.-dec.
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.C(O)C.[F:16][C:17]([F:50])([F:49])[C:18]1[CH:19]=[C:20]([CH:46]=[CH:47][CH:48]=1)[C:21]([NH:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:37]C(=O)OCC)=S)=[N:32][CH:33]=1)=[O:22]>CO>[NH2:37][C:35]1[N:34]=[C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[C:20]4[CH:46]=[CH:47][CH:48]=[C:18]([C:17]([F:16])([F:49])[F:50])[CH:19]=4)[CH:45]=[CH:44][CH:43]=3)=[CH:33][N:32]2[N:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2n1
Temperature: 60 °C
Yield: 122.2 %

Procedure:
To a solution of hydroxylamine hydrochloride (400 mg, 5.76 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.20 mL, 6.88 mmol) in methanol (8.0 mL)/ethanol (8.0 mL) was added ethyl ({[5-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (480 mg, 0.95 mmol) obtained above, and the mixture was stirred with heating at 60° C. for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and fractions containing the object product was concentrated under reduced pressure to give the title compound (0.48 g, quantitative) as a pale-yellow powder.
Reaction SMILES: C(C(C1C=CC(OC)=C(C=1)C=O)(C)C)#N.[ClH:16].Cl.C1([C@H]2[C@@H](N)CCCN2)C=CC=CC=1.Cl.Cl.[C:33]([C:35]1([C:38]2[CH:39]=[CH:40][C:41]([O:58][CH3:59])=[C:42]([CH:57]=2)[CH2:43][NH:44][C@H:45]2[CH2:50][CH2:49][CH2:48][NH:47][C@H:46]2[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:37][CH2:36]1)#[N:34]>>[ClH:16].[ClH:16].[C:33]([C:35]([C:38]1[CH:39]=[CH:40][C:41]([O:58][CH3:59])=[C:42]([CH:57]=1)[CH2:43][NH:44][C@H:45]1[CH2:50][CH2:49][CH2:48][NH:47][C@H:46]1[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([CH3:37])[CH3:36])#[N:34]
Reactant: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: COc1ccc(C(C)(C)C#N)cc1C=O
Agent: Cl
Agent: N[C@H]1CCCN[C@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 27 and Compound 3 in the same manner of Compound 5.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[N:3]=1.C([O-])(=O)C.[Na+].[Br-:16].[K+].BrBr>CO>[Br:16][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][C:4]2=[N:10][CH:9]=1
Reactant: Cc1ccn2ccnc2n1
Reactant: [Br-]
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccn2c(Br)cnc2n1
Yield: 63 %

Procedure:
7-Methylimidazo[1,2-a]pyrimidine (100 mg, 0.75 mmol) and sodium acetate (74 mg, 0.90 mmol) were dissolved in methanol (2 ml) which had been saturated with potassium bromide and this mixture was cooled to −10° C. before dropwise addition of bromine (132 mg, 0.83 mmol) over 5 min. On complete addition the mixture was quenched by addition of 1M sodium sulfite solution (2 ml) and the solvent removed in vacuo. The residue was treated with water (15 ml) and saturated sodium hydrogencarbonate solution (15 ml) and extracted with ethyl acetate (3×40 ml). The organics were combined then washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to give an off white solid. This solid was purified by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-2%) to give 3-bromo-7-methylimidazo[1,2-a]pyrimidine (100 mg, 63%) as a white crystalline solid: δH (400 MHz, CDCl3) 2.67 (3H, s), 6.87 (1H, d, J 7), 7.71 (1H, s), 8.27 (1H, d, J 7).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:42][CH2:43][O:44][Si:45]([C:58]([CH3:61])([CH3:60])[CH3:59])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:22]1[S:23][C:24]([C:27]2[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[C:29]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:28]=2)=[CH:25][N:26]=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>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[NH2:33][C:31]1[CH:32]=[C:27]([C:24]2[S:23][C:22]([N:21]([CH2:42][CH2:43][O:44][Si:45]([C:58]([CH3:61])([CH3:60])[CH3:59])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:26][CH:25]=2)[CH:28]=[C:29]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:30]=1
Reactant: CC(C)(C)[Si](OCCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cc(N3CCOCC3)cc([N+](=O)[O-])c2)s1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cc(N)cc(N3CCOCC3)c2)s1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of N,N-bis(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-[3-(morpholin-4-yl)-5-nitrophenyl]-1,3-thiazol-2-amine (999 mg, 1.147 mmol) in ethyl acetate (10 mL) and acetic acid (1.000 mL) at R.T., under nitrogen, was added palladium on carbon (122 mg, 0.115 mmol). The mixture was purged 3 times alternating between vacuum and H2. The reaction mixture was stirred under 1 atm H2 for 2 h. The system was evacuated with vacuum and purged 3 times alternating between vacuum and N2, and 3 mL DCM were added. The mixture was filtered through a pad of celite. The pad was rinsed with ethyl acetate and the filtrate concentrated. Residual AcOH was azeotroped with toluene (3×) to give 5-[3-amino-5-(morpholin-4-yl)phenyl]-N,N-bis(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-1,3-thiazol-2-amine as a yellow gum (958 mg, 1.139 mmol, 99%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C@@H](C4C=CC=CC=4)C)[CH2:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)N3CCOCC3)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccc([C@H]2CNCCO2)cc1)N1CCOCC1
Yield: 99.8 %

Procedure:
A solution of morpholin-4-yl-{4-[(2S)-4-((1R)-1-phenylethyl)-morpholin-2-yl]-phenyl}-methanone (465 mg, 1.20 mmol) and 20% palladium hydroxide on carbon (0.50 g) in ethanol (6.0 ml) was stirred under hydrogen atmosphere at room temperature for 10 hours. The mixture was passed through Celite column and the organic layer was concentrated under reduced pressure to yield morpholin-4-yl-((2S)-4-morpholin-2-yl-phenyl)-methanone (331 mg, 100%) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([NH:13][CH2:14][CH2:15][OH:16])=S)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[O:16][CH2:15][CH2:14][N:13]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(NC(=S)NCCO)c1=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(Br)cc(NC2=NCCO2)c1=O
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 1-(5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-3-(2-hydroxy-ethyl)-thiourea (306 mg, 1 mmol) in tetrahydrofuran (8 mL) was added aqueous 2N sodium hydroxide (1.25 mL, 2.5 mmol). With vigorous stirring a solution of para-toluene sulfonyl chloride (210 mg, 1.1 mmol) in tetrahydrofuran (4 mL) was added via drop-wise addition over 2 minutes. The material was stirred for 1 hour and then the solvent and volatiles were removed on the rotary evaporator. The remainder was taken up in ethyl acetate (25 mL) and water (15 mL) and shaken in a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×20 mL). The organic phases were combined, dried over magnesium sulfate, filtered and stripped. The crude was purifed by preparative TLC, eluted with 7% methanol in methylene chloride to provide the desired product as a light green-grey solid (243 mg). (M+H)+=272/274 m/e.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([F:17])[CH:5]=1)[CH3:3].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30](O)=[O:31])=[C:24](NCCC(C)C)[CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CCOC(OC(OCC)=O)=O>CN(C=O)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH:28]=[CH:29][C:30]([NH:1][C@@H:2]([C:4]2[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([F:17])[CH:5]=2)[CH3:3])=[O:31])=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)CCNc1cc(C(C)(C)C)ccc1C=CC(=O)O
Reactant: C=Cc1cc(C(C)N)cc(F)c1NS(C)(=O)=O
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: C=Cc1cc([C@@H](C)NC(=O)C=Cc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 11.6 %

Procedure:
N-[4-(1-Aminoethyl)-2-fluoro-6-vinylphenyl]methanesulfonamide (0.7 mmol, 25.3 mg), 3-[4-tert-butyl-2-(3-methylbutylamino)phenyl]acrylic acid (0.7 mmol, 15.27 mg), DEPC (0.08 mmol, 12.75 μl), and TEA (0.14 mmol, 19.51 μl) were added in DMF. The reaction mixture was stirred for 12 hrs. The reaction mixture was purified according to similar procedure of Example 21 to yield title product (36.1 mg, 100.0%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].Cl.[NH2:6][C@H:7]([CH:26]([CH3:28])[CH3:27])[C:8]([N:10]1[CH2:15][CH2:14][C@@:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([OH:16])[C:12]([CH3:25])([CH3:24])[CH2:11]1)=[O:9].C1COCC1>C(N(CC)CC)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C@@:13]2([OH:16])[CH2:14][CH2:15][N:10]([C:8](=[O:9])[C@H:7]([NH:6][C:3]([NH:2][CH3:1])=[O:4])[CH:26]([CH3:28])[CH3:27])[CH2:11][C:12]2([CH3:24])[CH3:25])=[CH:22][CH:21]=1
Reactant: CN=C=O
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)N[C@@H](C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with methyl isocyanate (3 μL), (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (20 mg) and THF (2 mL). Triethylamine (7.4 μL) was added and the reaction mixture was shaken overnight at rt. After this time, the resulting solution concentrated and purified by preparative silica gel chromatography (100% EtOAc to 20% MeOH/CH2Cl2) to provide Example 510. MS found: (M+H)+=396.3.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[S:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:12])=[O:11])=[O:4].[OH-].[Li+]>>[O:16]([CH2:15][CH2:14][CH2:13][S:10]([CH:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:3]([OH:4])=[O:2])(=[O:12])=[O:11])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C1CCCC1S(=O)(=O)CCCOc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C1CCCC1S(=O)(=O)CCCOc1ccccc1
Yield: 85.9 %

Procedure:
Prepared in the same manner as Example 14 from Example 12 (163 mg) and lithium hydroxide (105 mg) to give the title compound (134 mg) as a white solid.
Reaction SMILES: [C:1]([C:6]1[C:7](Cl)=[C:8]2[S:14][CH:13]=[CH:12][C:9]2=[N:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>O1CCOCC1.ClCCl>[C:1]([C:6]1[C:7]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[C:8]2[S:14][CH:13]=[CH:12][C:9]2=[N:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2ccsc2c1Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2ccsc2c1Nc1ccccc1C
Yield: 69.7 %

Procedure:
6-Butyryl-7-chlorothieno[3,2-b]pyridine (2.5 g, 0.0104 mol) and o-toluidine (2.23 g, 0,0208 mol) in 1,4-dioxan were heated under reflux for 3 hours. The solvent was evaporated under reduced pressure and the residue obtained was dissolved in dichloromethane (100 ml) and washed with 2NHCl (4×100 ml), then sodium carbonate solution (100 ml). The dichloromethane extracts were dried, filtered and evaporated under reduced pressure to give an oil, which crystallized on the addition of petroleum ether (b.p. 40°-60°). The solid was collected by filtration and dried to give 6-butyryl-7-(2-methylphenylamino)thieno[3,2-b]pyridine, (2.25 g), m.p. 114°-116°. 1 g was recrystallized from hexane to give an analytically pure sample, (0.7 g), m.p. 118°-120°.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:11]([O:10][P:9]([CH2:2][O:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])([O:13][CH2:14][CH3:15])=[O:16])[CH3:12]
Reactant: COC(=O)COCCl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(COCC(=O)OC)OCC
Temperature: 150 °C
Yield: 100.7 %

Procedure:
26 g (186 mmol) of methyl chloromethoxyacetate and 32 mL (186 mmol) of triethyl phosphite are placed in a round-bottomed flask and heated at 150° C. for 3 hours. The reaction progress is monitored by NMR. The reaction medium is concentrated under vacuum. 45 g (100%) of methyl (diethoxyphosphoryl)methoxyacetate are obtained directly in the form of a colorless liquid.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH:9]([O:12][C:13]1[N:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1)([CH3:11])[CH3:10]>CC(C)=O.C(OCC)C>[CH:9]([O:12][C:13]1[N:18]=[CH:17][C:16]([OH:2])=[CH:15][N:14]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)Oc1ncc(O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
An aqueous solution (5 mL) of potassium peroxymonosulfate (1.40 g, 2.27 mmol) was added dropwise to a solution of 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (Preparation 100, 500 mg, 1.89 mmol) in acetone (5 ml) under a nitrogen atmosphere at 0° C. The mixture was stirred at room temperature for 2 hours, then filtered, the filtrate diluted with water (30 mL) and extracted with EtOAc (1×20 mL). The organic layer was washed with brine (2×20 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The resulting oil was dissolved in dichloromethane and purified by silica gel chromatography eluting with 0 to 5% MeOH (with 10% aqueous ammonia) in dichloromethane to yield a solid. The solid was suspended in diethyl ether and evaporated to yield the title compound as a white solid (100 mg, 34%):