Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CN(C1C=CN=CC=1)C.O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[CH:12][CH:11]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(COC(=O)CCC(=O)O)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a solution of succinic anhydride (10 g, 0.1 mol) in CH3CN (200 mL) were added (4-methoxyphenyl)methanol (69.0 g, 0.5 mol) and DMAP (12.2 g, 0.1 mol). The reaction mixture was stirred for 3 h at about 30° C. and then diluted with water (700 mL) The resulting mixture was adjusted to pH=10 with saturated Na2CO3 solution and washed with ethyl acetate (300 mL×4) to remove an excess of (4-methoxyphenyl)methanol. The aqueous phase was adjusted to pH=2 with saturated citric acid solution and then extracted with ethyl acetate (200 mL×2). The combined extracts were dried over anhydrous Na2SO4 and concentrated to give product (21.0 g, 88% yield) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@H:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:21][CH:22]=1)[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@@H:11]2[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)[C@@H](N1CCCCC1)[C@H](O)C(C)(C)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccc2c(c1)[C@@H](N1CCCCC1)[C@H](O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
6-Acetyl-3,4-dihydro-2,2-dimethyl-trans-4-piperidino-2H-benzo[b]pyran-3-ol (1.00 g) was dissolved in methanol (10 ml) and water (2 ml) and treated with sodium borohydride (0.10 g) with stirring at room temperature during 5 minutes. After an additional 2 hours stirring, the reaction mixture was diluted with water (100 ml). Extraction using diethyl ether gave 1-hydroxy-1-[trans-2,2-dimethyl-3-hydroxy-4-piperidinochroman-6-yl]-ethane (1.00 g) which was dissolved in dry ether and treated with ethereal hydrogen chloride giving the hydrochloride salt (0.90 g) m.p. 179°-181° C. as a white powder from ethanol-ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:16](=O)[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([CH2:26][S:27][C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>CN(C)C=O.CCOCC>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][S:27][C:28]2[NH:30][C:16]([CH3:17])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:29]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(CSC(=N)N)cc1
Reactant: CCOC(=O)C(=Cc1cccc(OC)c1)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc(OC)c1
Reaction time: 4 h

Procedure:
A mixture of 2-[(3-methoxyphenyl)methylene]-3-oxobutanoic acid, ethyl ester (2.0 g., 8 mmole), S-(4-methoxybenzyl)thiopseudourea, hydrochloride (1.87 g., 8 mmole), and sodium acetate (0.67 g., 8 mmole) in dimethylformamide (10 ml.) is stirred at 70° for 4 hours. The cooled mixture is diluted with ether and washed with water, sodium bicarbonate, and brine. The dried solution is evaporated to give 2.85 g. of an impure oil. Flash chromatography using ethyl acetate:hexanes (1:3) gives 2.0 g. of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-4-(3-methoxyphenyl)- 6-methyl-5-pyrimidinedicarboxylic acid, ethyl ester as an oil.
Reaction SMILES: [Na:1].[S:2]([O:6][N:7]1[C:13](=[O:14])[N:12]2[CH2:15][C@H:8]1[CH2:9][CH2:10][C@H:11]2[CH2:16][NH:17]C(OC(C)(C)C)=O)([OH:5])(=[O:4])=[O:3].FC(F)(F)C(O)=O>ClCCl>[Na:1].[S:2]([O:6][N:7]1[C:13](=[O:14])[N:12]2[CH2:15][C@H:8]1[CH2:9][CH2:10][C@H:11]2[CH2:16][NH2:17])([OH:5])(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The sodium salt of (2S, 5R)-6-sulfooxy-2-(tert-butoxycarbonylaminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane (2.4 g, 0.006 moles) was suspended in dichloromethane (6 ml) and to the reaction mixture was slowly added trifluoroacetic acid (6 ml) at about 0-5° C. The reaction mixture was stirred between about 0-5° C. for additional 2 hours. The solvent and excess trifluoroacetic acid was evaporated under vacuum below 40° C. to approximately ⅓ of its original volume to provide pale yellow oily residue. This oily residue was triturated with diethyl ether and ether was decanted (40 ml×2). The crude solid was again triturated with dichloromethane (40 ml×2) and solvents were decanted. The final solid was dried under vacuum below 40° C. to furnish 2.2 g of sodium and trifluoroacetic acid salt of (2S, 5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo [3.2.1]octane (X) (90% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:27])[N:9]3[CH2:13][CH:12]([CH2:14][N:15]4[CH2:20][CH2:19][C@H:18]([OH:21])[C@H:17]([CH2:22][NH:23]C(=O)[O-])[CH2:16]4)[C:11]=1[C:10]=23.FC(F)(F)C(O)=O>ClCCl>[NH2:23][CH2:22][C@H:17]1[C@@H:18]([OH:21])[CH2:19][CH2:20][N:15]([CH2:14][CH:12]2[C:11]3=[C:2]([F:1])[CH:3]=[N:4][C:5]4[CH:6]=[CH:7][C:8](=[O:27])[N:9]([C:10]=43)[CH2:13]2)[CH2:16]1
Reactant: O=C([O-])NC[C@@H]1CN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@@H]1CN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
A suspension of 1,1-dimethylethyl({(cis-1-[(3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-hydroxy-3-piperidinyl}methyl)carbamate (0.175 g, 0.405 mmol) in dichloromethane (2 ml) was treated with trifluoroacetic acid (1 ml) and stirred at room temperature for 20 min. The reaction mixture was evaporated and then redissolved using a 4:1 dichloromethane:methanol solution. The organic phase was then treated with aqueous sodium bicarbonate solution. The aqueous phase was extracted 10 times with a 4:1 dichloromethane:methanol solution and then the combined organic phases were dried and the solvent was removed under reduced pressure and the residue was subjected to column chromatography on silica gel using a dichloromethane, methanol and ammonia gradient to provide the desired compound (0.08 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[C:5]([CH3:16])[N:4]([C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:20]=[CH:19][N:18]=2)[N:3]=1.[CH2:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:7][C:6]3[C:2]([CH3:1])=[N:3][N:4]([C:17]4[N:22]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)[CH:20]=[CH:19][N:18]=4)[C:5]=3[CH3:16])=[CH:9][CH:10]=2)[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1Oc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1Oc1ccc(CN2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.4 %

Procedure:
To a solution of 4-[3,5-dimethyl-1-(4-pyridin-2-yl-pyrimidin-2-yl)-1H-pyrazol-4-yloxy]-benzaldehyde (0.545 g, 1.47 mmol) and 1-benzylpiperazine (0.310 g, 1.76 mmol) in dichloroethane (10 mL) was added sodium triacetoxyborohydride (0.436 g, 2.06 mmol). The reaction mixture was stirred at room temperature for 17 hours. The solution was diluted with methylene chloride (50 mL) and washed with saturated sodium hydrogencarbonate (2×30 mL) and brine (50 mL). The organic phase was dried (magnesium sulfate), filtered, and concentrated to afford a yellow oil. Flash chromatography over silica (2 M ammonia in methanol/methylene chloride) provided 0.183 g (23%) of the product as a white foam: 1H NMR (CDCl3) δ 8.94-8.93 (m, 1H), 8.75 (d, J=3.9 Hz, 1H), 8.46 (d, J=7.9 Hz, 1H), 8.25 (d, J=3.9 Hz, 1H), 7.90-7.87 (m, 1H), 7.46-7.43 (m, 1H), 7.31-7.21 (m, 7H), 6.89 (d, J=8.5 Hz, 2H), 3.52 (s, 2H), 3.47 (s, 2H), 2.68 (s, 3H), 2.48 (br s, 8H), 2.21 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[N:26]3[C:33](=[O:43])[N:34]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)[N:35]=[C:25]3[C:24]=2[CH:23]=1>CN(C=O)C.CCN(CC)CC.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>[CH2:1]([C:22]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[N:26]3[C:33](=[O:43])[N:34]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)[N:35]=[C:25]3[C:24]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1ccccc1
Reactant: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc3c4cc(Cc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a stirred solution of benzyltributyltin (69 mg, 0.184 mmol) and 8a (19.5 mg, 0.0525 mmol) in a mixture of 2 mL of DMF and 1 mL of NEt3, was added Pd(PPh3)4 (6.0 mg, 5.3 μmol). The seal tube was sealed under argon and the mixture was stirred at 110° C. for 18 h. The reaction the mixture was cooled and concentrated to dryness in vacuo and the crude product was purified by chromatography on a silica gel column. Elution with n-heptane/EtOAc (2:1) as eluent yielded 16a as a white solid (13 mg, 65%). mp: 299° C.,
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9]2)[CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[NH:26][CH2:25]2>>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]2[CH:7]=[C:2]([N:26]3[CH2:25][C:24]4[C:28](=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=4)[C:27]3=[O:31])[CH:3]=[N:4][CH:5]=2)[CH2:9]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2cncc(Br)c2)C1
Reactant: O=C1NCc2cc(Cl)ccc21
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2cncc(N3Cc4cc(Cl)ccc4C3=O)c2)C1

Procedure:
In analogy to the procedures described for the preparation of example 137, 3-bromo-5-[(R)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-pyridine (example 137 [B]) has been reacted with 5-chloro-2,3-dihydro-isoindol-1-one to give 2-{5-[(R)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-pyridin-3-yl}-5-chloro-2,3-dihydro-isoindol-1-one, which was then deprotected with 4M HCl in dioxane to give the title compound as light yellow solid. MS: 330.1 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:10]([CH:21]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:24])=O)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[CH2:39]([O:46][NH2:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:10]([CH:21]([CH:25]([CH3:27])[CH3:26])[C:22]([NH:47][O:46][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:24])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(C2CN(Cc3ccccc3)C(=O)N2C(C(=O)O)C(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C2CN(Cc3ccccc3)C(=O)N2C(C(=O)NOCc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (150 mg; 0.39 mmol) was introduced into DMF (10 ml) and cooled to 0° C. Then N,N-diisopropylethylamine (202 mg; 1.56 mmol), O-benzylhydroxylamine hydrochloride (125 mg, 0.78 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 223 mg; 0.58 mmol) were added, and the mixture was stirred at 0° C. for 2 h. The reaction solution was then concentrated and partitioned between dilute HCl solution/EtOAc and extracted with EtOAc (2×). The combined organic phases were dried over MgSO4, and the solvent was removed in a rotary evaporator. Purification by chromatography resulted in 2-(3-benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-benzyloxy-3-methylbutyramide (116 mg; 0.24 mmol). MS: 488.25 (M+H); Rt: 3.50 min (method: gradient 95% H2O (0.05% TFA) to 95% acetonitrile over 3.5 min, 95% acetonitrile for 1.0 min, 5% acetonitrile 1.0 min; flow rate 0.5 ml/min; column 1 μL (Merck Purospher 5μ 2×55 mm); 30° C.)
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[C:34]([N:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@@H:2]([NH:1][C:45]([CH:43]2[CH2:44][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42]2)=[O:46])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH2:22][CH:23]3[CH2:24][CH2:25]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCN(c3ccccc3N(CC3CC3)S(C)(=O)=O)CC2)C1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(4-Chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl)-2-oxoethyl]carbamoyl}-azetidine-carboxylate was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one (Step 3) (220 mg, 0.46 mmol), according to the procedure for Preparation XIX using Boc-azetidine-3-carboxylic acid (100 mg, 0.50 mmol) (Peptech)., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (275 mg, 0.925 mmol), HOAT (64 mg, 0.470 mmol), and DMF (7 mL). The compound was isolated (294 mg). MS (ESI, pos. ion) m/z: 674 (M+H), (ESI, neg. ion) m/z: 672 (M−H). Calc'd for C33H44ClN5O6S: 674.25.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:17][CH2:9][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][CH:5]=1
Reactant: Cc1ccc(Cl)c(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)nc1Cl
Temperature: 80 °C
Yield: 97.9 %

Procedure:
To a solution of 2,3-dichloro-6-methylpyridine (2 g, 12.3 mmol) in carbon tetrachloride (40 mL) was added NBS (2.64 g, 14.8 mmol) followed by AIBN (40 mg, 0.24 mmol). The reaction heated to 80° C. under nitrogen for 3.5 hours. The reaction was cooled and concentrated in vacuo. The residue was sonicated in heptanes and filtered. The filtrate was eluted through a pad of silica using 10% TBME in heptanes to afford the title compound (2.90 g). The crude material was taken on directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[N:3]=1.[Br:9]Br>C(O)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:8])[CH:5]=[CH:6][C:7]=1[Br:9]
Reactant: Nc1cccc(O)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1nc(O)ccc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
Under an argon atmosphere 2-amino-6-hydroxy-pyridine (19.6 g, 178 mmol) was suspended in acetic acid (100%, 390 mL). Br2 (9.2 mL, 178 mmol) was added at 20° C. over 5 min. The green suspension was stirred at RT for 20 min. The mixture was poured onto H2O (400 mL) and filtered. The filtrate was mixed with brine (200 mL) and extracted with EtOAc (10×400 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated to afford 6-Amino-5-bromo-pyridin-2-ol as a yellow solid (23 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH:42]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(CCN4CCOCC4)c3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 36.9 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford desired N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)benzamide (0.045 g, 36.9%).
Reaction SMILES: [Na].C(O)C.[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([CH2:13][C:14]#[N:15])[CH:10]=[CH:11][CH:12]=1.[C:18]1([CH2:24][C:25](OCC)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[F:5][C:6]([F:16])([F:17])[C:7]1[CH:8]=[C:9]([CH:13]([C:25]([CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[C:14]#[N:15])[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: N#CC(C(=O)Cc1ccccc1)c1cccc(C(F)(F)F)c1
Yield: 73.5 %

Procedure:
In this example, 4.91 g of metallic sodium was added to 110 ml of anhydrous ethanol at room temperature and stirred until all of the sodium dissolved. A mixture containing 18.76 g of (3-trifluoromethylphenyl)acetonitrile and 21.73 g of ethyl phenylacetate was then added dropwise and the resulting mixture was stirred at reflux for about 18 hours. The mixture was then poured into 300 ml water and extracted three times with ethyl ether. The pH of the extracted aqueous layer was adjusted to a pH of about 1 with aqueous 10 wt. % hydrochloric acid and again extracted three times with ethyl ether. The organic layer was washed twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness under vacuum affording 22.6 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[NH3:13]>O1CCCC1.CO>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[NH2:13]
Reactant: N
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A solution of the 1,3,5-trifluoro-2-nitrobenzene (7.08 g, 39.98 mmol) in tetrahydrofuran (50 mL) was stirred at 0 degrees Centigrade while a solution of 7N ammonia in methanol (23 mL) was added. The reaction mixture was stirred overnight in a sealed tube. The mixture was filtered, and the solvent removed to give a red-orange solid which was purified by silica gel column chromatography using 2:1 hexanes/ethyl acetate to give 6.27 g of 3,5-difluoro-2-nitroaniline.
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH2:10].C([O:18][C:19](=O)[NH:20][C:21]1[S:22][C:23]([F:36])=[C:24]([CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:25]=1)(C)(C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:10][C:19]([NH:20][C:21]1[S:22][C:23]([F:36])=[C:24]([CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:25]=1)=[O:18]
Reactant: COc1ccc(SCc2nc(NC(=O)OC(C)(C)C)sc2F)cc1
Reactant: NCc1cccc(F)c1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(SCc2nc(NC(=O)NCc3cccc(F)c3)sc2F)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 2 M trimethylaluminum in toluene (0.68 mL, 1.4 mmol) was treated with 3-fluorobenzylamine (0.16 mL, 1.4 mmol), followed by a solution of [5-fluoro-4-(4-methoxy-phenylsulfanylmethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (250 mg, 0.68 mmol), obtained above, in anhydrous toluene (3 mL). The resulting solution was heated at 80-100° C. for 3 hours. The cooled reaction mixture was hydrolyzed by sequential addition of: water (50 uL); 15% aqueous sodium hydroxide (50 uL); and water (150 uL). After stifling overnight, the granular aluminum salts were removed by filtration. The filtrate was concentrated and purified by silica gel chromatography (EtOAc) to afford Intermediate 106: 1-(3-fluoro-benzyl)-3-[5-fluoro-4-(4-methoxy-phenylsulfanylmethyl)-thiazol-2-yl]-urea as a pale yellow solid (168 mg, 59% yield).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][CH:6]1[NH:12]S(C1C=CC(C)=CC=1)(=O)=O)(=O)[NH2:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[I:11][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH:4]=[C:1]([NH:2][C:23](=[O:25])[CH3:24])[N:12]=2)[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)NC2C=CC(I)=CN2CC(N)=O)cc1
Product: CC(=O)Nc1cn2cc(I)ccc2n1
Temperature: 25 °C

Procedure:
A mixture of the product from Step B (300 mg, 0.70 mmol) and 1.0 mL of acetic anhydride was warmed at reflux for 2.5 h. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous brine, dried (magnesium sulfate) and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica gel, 7% methanol/dichloromethane) to afford the title compound as a pale yellow powder. LC/MS 301.9 (M+1).