Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=3[C:9](=[O:17])[N:8]([CH3:18])[CH2:7][C:6]=12.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(NCC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:16][C:15]1[C:10]2[C:9](=[O:17])[N:8]([CH3:18])[CH2:7][C:6]3[N:5]([CH:4]=[N:3][C:2]=3[C:23]#[C:22][C:20]([OH:24])([CH3:21])[CH3:19])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: C#CC(C)(C)O
Reactant: CN1Cc2c(Br)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.26 g (10 mmol) of 3-bromo-7-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux overnight with 1.10 g (12 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 20 ml of diethylamine and 15 ml of methylene chloride. The reaction mixture was evaporated and the residue was dissolved in methylene chloride. After chromatography of the solution on silica gel while eluting with ethyl acetate and crystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 194°-195°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[OH:13][CH:12]1[CH2:11][O:10][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)[O:6][CH2:14]1
Reactant: O=Cc1cccc(F)c1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: OC1COC(c2cccc(F)c2)OC1
Yield: 73.2 %

Procedure:
A mixture of 3-fluorobenzaldehyde (24.8 g, 0.2 mole), glycerol (18.4 g, 0.2 mole) and 40% sulfuric acid (2.0 ml) in benzene (200 ml) was heated with stirring under a Dean-Stark apparatus until water ceased to collect (approximately 2.5 hours). The mixture was cooled, neutralized with potassium carbonate and, after adding 200 ml of ether, washed with water (3 × 100 ml). The washed solution was dried over magnesium sulfate and concentrated under reduced pressure to give 29.0 g of colorless oil which was distilled under 0.025 mm using a short path distillation apparatus to give 18.9 g, nD24 1.5160, of 5-hydroxy-2-(3-fluorophenyl)-1,3-dioxane which distilled at a bath temperature of 86°-105° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[C:12]([C:28]([F:31])([F:30])[F:29])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:27][N:26]1[C:22]([C@H:18]2[CH2:19][CH2:20][CH2:21][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:8])=[O:9])=[CH:11][C:12]=2[C:28]([F:31])([F:29])[F:30])=[CH:23][CH:24]=[N:25]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(C(F)(F)F)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)cc1C(F)(F)F
Yield: 53.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide (123 mg, 0.199 mmol) prepared in Example 21b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (50.0 mg, 54%) as a colorless solid.
Reaction SMILES: [CH:1]([C:9]1[C:17]2[CH2:16][CH2:15][C:14]([O:18][C:19]3[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=3)=[CH:13][C:12]=2[NH:11][N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[N:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CN(C=O)C>[CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:20]=[C:21]([NH:25][C:32]([C:30]4[S:31][C:27]([CH3:26])=[CH:28][N:29]=4)=[O:33])[CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cnc(C(=O)O)s1
Reactant: Nc1cccc(OC2=Cc3[nH]nc(C=Cc4ccccc4)c3CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CN(C)C=O
Product: Cc1cnc(C(=O)Nc2cccc(Oc3ccc4c(C=Cc5ccccc5)n[nH]c4c3)c2)s1

Procedure:
3-(3-Styryl-4,5-dihydro-1H-indazol-6-yloxy)-phenylamine was converted to 5-methyl-thiazole-2-carboxylic acid {3-[1-(5-methyl-thiazole-2-carbonyl)-3-styryl-1H-indazol-6-yloxyl-phenyl}amide by treatment with 5-methyl-thiazole-2-carboxylic acid and HATU (o-(2-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) in DMF and analogous work-up, DDQ treatment and isolation to Example 4(a), step (iv) (50% yield): 1H NMR (DMSO-d6) δ 10.85 (s, 1H), 8.45 (d, 1H, J=9.8 Hz), 8.24 (m, 3H), 7.99-7.62 (m, 6H), 7.54-7.34 (m, 5H), 6.96 (d, 1H, J=8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15]>CC(N(C)C)=O>[I:1][C:2]1[C:7]2[C:8](=[O:9])[N:14]([CH3:16])[CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2cccc(I)c2c(=O)o1
Solvent: CC(=O)N(C)C
Product: CN1CC(=O)Nc2cccc(I)c2C1=O

Procedure:
A mixture of 8.7 g (0.03 mol) of 6-iodoisatoic acid anhydride, 3.2 g (0.036 mol) of sarcosine and 25 ml of dimethylacetamide is heated to boiling under reflux for 1 hour. After cooling and dilution with water, the mixture is extracted with chloroform. The chloroform extracts are dried and evaporated. After recrystallization of the crude product from methylene chloride/ether, there is obtained 3,4-dihydro-6-iodo-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 214°-217°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:10]1([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Clc1ccc(-c2ccccc2)cc1Cl
Temperature: 120 °C
Yield: 30.4 %

Procedure:
A mixture was prepared of 1-Bromo-3,4-dichlorobenzene (20.0 g, 88.5 mmol), phenylboronic acid (13.5 g, 110.6 mmol), triphenylphosphine (2.32 g, 8.85 mmol), potassium carbonate (30.58 g, 221.25 mmol), 150 mL xylenes, and 150 mL water. The mixture was stirred and nitrogen bubbled into it for 20 minutes. Palladium acetate was added (0.99 g, 4.425 mmol) and the mixture was heated at 120° C. under nitrogen overnight. Cooled to room temperature and diluted with water and dichloromethane. The mixture was filtered through Celite and the Celite was washed with water and dichloromethane. The layers were separated and the aqueous layer extracted with dichloromethane. The organic layers were dried over magnesium sulfate, filtered, and evaporated to yield a brown oil. The crude material was purified by column chromatography eluting with hexanes. The cleanest fractions containing product were collected. Obtained 6 g (30%) of clean product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH2:13][CH2:12]3)=[CH:5][CH:4]=1.[Br:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1.Cl>ClCCl>[Br:20][C:21]1[S:25][C:24]([S:26]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)s1)N1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.25 g commercially available 5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-1H-indole were dissolved in 10 ml dichloromethane. Then 2.5 ml diidopropylethylamine were added. Then 1.37 g of commercially available 5-Bromo-thiophene-2-sulfonyl chloride dissolved in 5 ml dichloromethane were at 0° C. The mixture was stirred at room temperature for three hours. Then the mixture was poured on 100 ml 1M HCl and extracted five times with portions of 50 ml dichloromethane. The combined organic extracts were washed with 100 ml saturated NaHCO3 solution. The organic layer was then dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by chromatography on silica gel to obtain 2.1 g of 1-(5-Bromo-thiophene-2-sulfonyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20](=[O:22])(=[O:21])[NH2:23])[CH:15]=2)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NS(=O)(=O)c2ccc(Br)cc2Cl)c1

Procedure:
Using a method analogous to Method E, using 4-bromo-2-chlorobenzenesulfonyl chloride and 3-aminobenzenesulfonamide, the title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10]Cl.[Na+].[I-:14]>CC#N>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][I:14]
Reactant: Nc1ccc(Cl)cc1C(=O)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ccc(Cl)cc1C(=O)CI
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.2 %

Procedure:
To a solution of 11.208 g (54.93 mM) of 2'-amino-2,5'-di-chloroacetophenone in 281 ml of CH3CN is added 24.7 g (165 mM) of NaI, and the mixture is stirred at room temperature for 2.5 hr. and concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with aqueous Na2S2O3, and brine in order, dried and concentrated to give 16.1 g (Yield: 99.2%) of 2'-amino-5'-chloro-2-iodoacetophenone as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](N(C)C)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C>C1COCC1>[C:15]([NH:19][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of 2,4-dichloro-quinazoline obtained in step B of example 1 (4 g, 20 mmol) in THF (50 mL) were added tert-butyl amine (2.15 mL, 20.5 mmol) and diisopropylethylamine (3.5 mL, 21 mmol). The mixture was stirred at ambient temperature for 2 hr. The mixture was concentrated and the residue was dissolved in EtOAc. The organic layer was washed with water, dried over Na2SO4, and filtered. The mixture was concentrated to give tert-butyl-(2-chloro-quinazolin-4-yl)-amine as a white solid (3 g, 64%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2C2C=CC=CC=2)[CH:4]1[OH:18])[CH3:2].C(N([CH2:24][CH3:25])CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:3]1([C:25]2[CH:24]=[CH:4][CH:3]=[CH:1][CH:2]=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[OH:18])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCC1Cc2c(-c3ccccc3)cccc2C1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCC1(c2ccccc2)Cc2ccccc2C1O
Temperature: 0 °C
Yield: 133.4 %

Procedure:
To a 1-liter four-necked round flask (equipped with a stirrer, a dropping funnel and a thermometer) were fed 29.3 g (123.9 mmol) of 2-ethyl-1-hydroxy-4-phenylindane, 51.6 g (371.4 mmol) of triethylamine, 0.75 g (6.3 mmol) of 4-dimethylaminopyridine and 294 ml of methylene chloride. Then, a solution obtained by dissolving 19.2 ml (247.5 mmol) of methanesulfonyl chloride in 19.5 ml of methylene chloride was dropwise added slowly to the system while cooling with ice in a nitrogen atmosphere. After the addition was completed, the resulting mixture was reacted for another 3.5 hours at the same temperature. The reaction mixture was poured in 500 ml of ice water, then the organic phase was separated, and the aqueous phase was further extracted twice with 150 ml of methylene chloride. The whole organic phase was successively washed with a saturated NaHCO3 solution and a saturated salt solution, and dried with anhydrous Na2SO4. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography (developed with hexane), to obtain 19.7 g of the aimed product (mixture of two kinds of isomers) as a light yellow liquid (yield: 73%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[C:3]([CH:12]=O)=[N:2]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:12]1[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[NH:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=2)[NH:1][N:2]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1cccc2[nH]nc(C=O)c12
Product: c1ccc2[nH]c(-c3cccc4[nH]nc(-c5nc6ccccc6[nH]5)c34)nc2c1

Procedure:
The title compound is prepared using the procedure described in Example 4 from 1H-indazole-3,4-dicarbaldehyde and an excess of 1,2-diaminobenzene.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.Cl[P:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O1CCCC1>[CH3:9][C:7]1[CH:8]=[C:3]([P:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=[C:5]([CH3:10])[CH:6]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(P(c2ccccc2)c2ccccc2)c1

Procedure:
In a 3-neck 1 liter flask equipped with blade stirrer, nitrogen inlet, Claissen adaptor, condenser, drying tube and constant pressure dropping funnel, was placed 6.67 g (0.274 g atoms) of magnesium turnings. Under a nitrogen flow, the glassware was dried with heating via a heat gun. To the magnesium was added a portion of a solution of 55.5 g (0.30 mol) of 5-bromo-m-xylene in 150 ml dry THF (tetrahydrofuran). Reaction was initiated with external heating and the balance of the solution was added dropwise over approximately 30 min, maintaining gentle reflux. The mixture was then stirred for another 1 hr after which a solution of 41.3 g (0.188 mol) of chlorodiphenylphosphine in 150 ml of dry THF was added over approximately 10 min. The mixture was then heated at reflux for 2 hr, cooled and poured into ice. The mixture was neutralized with concentrated HCl and nitrogen was bubbled through the mixture overnight. The organic layer was taken up in methylene chloride and separated from the aqueous layer. Concentrating the organic layer afforded an oil which crystallized on standing. After triturating with an equal volume of methanol, the solid was collected and recrystallized from methanol. The yield of 3,5-dimethylphenyldiphenylphosphine was 37.5 g (68.7% of theory); mp=67°-9° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)(C(C)(C)C)(C)C.O[C@@H:22]([CH2:35][CH:36]1[CH2:39][CH2:38][CH2:37]1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:24]>>[CH:9]([C@@H:10]1[C@@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][N:12]([C@H:22]([CH2:35][CH:36]2[CH2:39][CH2:38][CH2:37]2)[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[O:24])[CH2:11]1)=[O:8]
Reactant: COc1ccc(COC(=O)[C@@H](O)CC2CCC2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Product: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1

Procedure:
The title compound was prepared from 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (from EXAMPLE 1, Step E) and 4-(methoxy)benzyl 2-(S)-hydroxy-3-(cyclobutyl)propanoate (from EXAMPLE 19, Step E) using procedures analogous to those described in EXAMPLE 1, Steps G-I.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>ClCCl>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][C:19](=[O:21])[NH:58][CH2:57][C:56]([F:60])([F:59])[F:55])([CH3:11])([CH3:12])[CH3:13]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(F)(F)F
Reaction time: 24 h

Procedure:
DIPEA (15 ml) is added to a solution of N-(tert-butoxycarbonyl)glycine (5.0 g), PYBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 16.3 g) and 2,2,2-trifluoroethylamine (2.47 ml) in dichloromethane (48 ml). After 24 hours at room temperature, the reaction is quenched with water and extracted three times with dichloromethane. The combined organic phases are washed with HOC (2M), Na2CO3 (1M) and a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified by column chromatography (450 g) eluting with a mixture of ethyl acetate and hexane (2:3 to 3:2) to yield [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (3.89 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(O)cc3OCC3CC3)ncnc12
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(O)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-hydroxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A188) and propionyl chloride the title compound is obtained as colorless solid
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]1([C@H:17]([CH2:19][OH:20])[NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][C@H:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:19][OH:20])=[O:6]
Reactant: O=C(Cl)c1cccc(I)c1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccc(I)c1
Reaction time: 3 h
Yield: 63.7 %

Procedure:
To a vigorously stirred solution of 3-iodobenzoyl chloride (16.79 g, 63 mmol) in dichloromethane (300 ml) was rapidly added a solution of (R)-(-)-2-phenylglycinol (8.64 g, 63 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 3 hours and crude product collected by filtration. Recrystallization from isopropyl alcohol gave (+)-2-(3-iodobenzamido)-2(R)-phenylethan-1-ol as white needles (14.74 g, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:21]1[O:23][C@H:22]1[CH2:24]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:24][C@H:22]2[CH2:21][O:23]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cccc(O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCc1cccc(OC[C@H]2CO2)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
To an acetone solution (0.15 M, 170 mL) of 3-(3-Hydroxy-phenyl)-propionic acid ethyl ester (5.0 g, 25.77 mmol) was added K2CO3 (10.69 g, 77.32 mmol), and the mixture was heated to reflux for 30 min. After cooling this mixture to RT, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (6.68 g, 25.77 mmol) was added, and the resulting mixture was heated to reflux overnight. After cooling to room temperature, the solids were removed by filtration and washed well with ethyl acetate. The filtrate was concentrated and partitioned between ethyl acetate and 1N HCl. The organic portion was washed successively with 5% NaHCO3 and brine, dried (MgSO4), filtered and concentrated to a solid. Purification by FCC (30% ethyl acetate/hexanes) gave the product as a white solid in 93% yield (6.0 g). LCMS (m/z) M+H: 187
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:17])=[C:7]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH:8]=1.Cl[C:19]1[N:20]=[C:21]2[CH:29]=[CH:28][N:27]=[CH:26][C:22]2=[N:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:17])=[C:7]([C:9]([CH:11]2[CH2:12][CH2:13][N:14]([C:19]3[N:20]=[C:21]4[CH:29]=[CH:28][N:27]=[CH:26][C:22]4=[N:23][C:24]=3[Cl:25])[CH2:15][CH2:16]2)=[O:10])[CH:8]=1
Reactant: O=C(c1cc(Cl)ccc1F)C1CCNCC1
Reactant: Clc1nc2ccncc2nc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cl)ccc1F)C1CCN(c2nc3ccncc3nc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
A mixture of (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanone hydrochloride (153 mg, 0.550 mmol), 2,3-dichloropyrido[3,4-b]pyrazine (100 mg, 0.500 mmol) and DIPEA (261 μL, 1.500 mmol) in DCM (1.67 mL) was stirred at rt for 30 min. The mixture was partitioned between aqueous NH4Cl and EtOAc. The organic layer was filtered through a pad of silica, washing with EtOAc, and the filtrate was concentrated under reduced pressure to give (5-chloro-2-fluorophenyl)(1-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone (205.5 mg) as an orange solid. ESI-MS m/z [M+H]+ 405.2.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Cl)=[CH:17][CH:16]=1>C1COCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:4]([C:6]2[S:10][C:9]([CH3:11])=[N:8][C:7]=2[CH3:12])=[O:5])=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1sc(C)nc1C
Reactant: Cl[Mg]c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a flask containing N-methoxy-N,2,4-trimethylthiazole-5-carboxamide (510 mg, 2.55 mmol, Intermediate 17: step a) was added THF (18 mL) and the solution was cooled to 0° C. To this solution was added (4-chlorophenyl)magnesium chloride (1 M in diethylether, 3.3 mL, 3.3 mmol). A homogeneous yellow mixture resulted and was allowed to warm to room temperature over 15 minutes. After 2 hours, the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (100% DCM increasing to 10% EtOAc-DCM) provided the title compound as a white solid.