Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C1COCC1>ClCCl>[CH3:5][O:6][C:7]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:8]=1[CH:9]=[O:10]
Reactant: COc1cc(C#N)ccc1C(=O)O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cc(C#N)ccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
Thionyl chloride (50 ml) was added to 2-methoxy-4-cyano benzoic acid (Tetrahedron Letters, 1986, 27(49), 5997–6000) (8 g, 45.2 mmol) in dichloromethane (70 ml) and the solution was refluxed for 5 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude benzoyl chloride was dissolved in diglime (120 ml), cooled at −78° C. and 1M lithium tritertbutoxyaluminium hydride in THF (46 ml, 46 mmol) was added dropwise in 3 h. Stirring was continued for 30 min at −78° C. then the reaction was allowed to reach 0° C. and quenched with water (15 ml) and 2N NaOH (15 ml). The reaction mixture was stirred for 1 h, filtered and the organic phase was removed under reduced pressure. The crude residue was purified by column chromatography eluting with n-hexane/ethyl acetate 80:20 to give 4 g of the title compound (yield 55%) as a yellow powder, mp=112–114° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=2[N:7]=1.[CH2:26]([NH:28][C:29](=[O:46])[NH:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[CH2:26]([NH:28][C:29](=[O:46])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[C:5]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=3[N:7]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 120 °C
Yield: 59.4 %

Procedure:
To a solution of (S)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (intermediate 4) (576 mg, 1.56 mmol) and 4-(3-ethylureido)phenylboronic acid pinacol ester (498 mg, 1.72 mmol) in DME/EtOH/H2O (12/5/3) (15 mL) was added Pd(PPh3)2(Cl)2 (55 mg, 0.078 mmol) and Na2CO3 (496 mg, 4.68 mmol). The reaction mixture was then heated by microwave at 120° C. for 1 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with aqueous NaHCO3 and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (20-50% EtOAc/Petroleum Ether 40-60) to yield a yellow solid (460 mg, 59%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[N:6][N:5]=[C:4]1[CH2:8]O)[CH3:2].S(Cl)([Cl:12])=O>>[ClH:12].[Cl:12][CH2:8][C:4]1[N:3]([CH2:1][CH3:2])[CH:7]=[N:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: CCn1cnnc1CO
Product: CCn1cnnc1CCl
Product: Cl

Procedure:
To 4-ethyl-3-hydroxymethyl-4H-1,2,4-triazole (4.6 g), thionyl chloride (36 ml) was slowly added at 0° C. The mixture was heated to reflux for 1 hour, and concentrated under reduced pressure. To the residue was added ethyl acetate and ethanol, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate, to give 3-chloromethyl-4-ethyl-4H-1,2,4-triazole hydrochloride (4.22 g) as orange crystals.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([O:40][C:41](=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:28]=[CH:29][C:30]([O:32]CC1C=CC=CC=1)=[O:31])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]>C(OCC)(=O)C.[Pd]>[C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([O:40][C:41](=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(C=CC(=O)OCc1ccccc1)COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OC(CCC(=O)O)COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
A solution of benzyl 5-(N-FMOC-L-valyloxy)-4-stearoyloxy-2-pentenoate (3.8 g, 4.69 mmole) in 50 ml ethyl acetate was hydrogenated with 10% palladium on charcoal (0,5 g) at normal pressure for five hours at room temperature. The catalyst was filtered and washed with ethyl acetate and 1,4-dioxane. The solution was evaporated under reduced pressure Yield: 3.3 g=99%
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](O)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:12][CH2:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of 1,2,3,4-tetrahydro-2-naphthoic acid (2.50 g, 14.2 mmol) in 100 ml THF was treated with LiAlH4 (681 mg, 17.04 mmol) and the reaction mixture was heated at reflux for 5 hours. The suspension was cooled to 0° C. and quenched by addition of solid Na2SO4▪10H2O. The mixture was stirred at room temperature for 4 hours. The solid was removed by filtration. Concentration of filtrate in vacuo gave a yellowish oil (2.28 g, 98.8%); 1H NMR (CDCl3, 300 MHz) δ1.43 (m, 1H), 2.00 (m, 2H) 2.51 (dd, J1=16.5 Hz, J2=10.8 Hz, 1H), 2.85 (m, 3H), 3.65 (dd, J1=6.3 Hz, J2=1.2 Hz, 2H), 7.09 (s, 4H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH2:10])=S)=[CH:3][CH:2]=1.CC(C)=O.C[I:17].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>CCOCC>[IH:17].[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([NH:7][C:8]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[NH:10])=[CH:3][CH:2]=1
Reactant: Cc1ccc(NC(N)=S)cc1
Reactant: C1CCNC1
Reactant: CI
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cc1ccc(NC(=N)N2CCCC2)cc1
Product: I

Procedure:
4-Tolylthiourea (33.2 g., 0.2 mole) in 200 ml. acetone is heated under reflux for 3 hrs. with methyliodide (31.4 g., 0.221 mole). Solvent is removed in vacuo and the resulting 2-methyl-1-(4-tolyl)-2-thiopseudourea hydroiodide dissolved in 200 ml. tert-butanol. Pyrrolidine (28.4 g., 0.4 mole) is added and the mixture heated at reflux for 18 hrs. The reaction mixture is cooled, diluted with ether and the resulting solid separated. Recrystallization from acetone-ether affords N-(4-tolyl)-1-pyrrolidinecarboximidamide hydroiodide, m.p. 166°-168° C. Conventional treatment of the salt in CH2Cl2 with aqueous (10-20%) NaOH affords the corresponding free base.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[C:13]1(/[CH:19]=[CH:20]/B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=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>[CH:20](/[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1)=[CH:19]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: O=C1COc2ccc(Br)nc2N1
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C1COc2ccc(/C=C/c3ccccc3)nc2N1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.0 g, 26.3 mmole) and trans-2-phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in 1,4-dioxane (150 mL) and the solution was degassed with argon. (Ph3P)4Pd (230 mg, 0.2 mmole) was added, followed by a solution of potassium carbonate (6.9 g, 50 mmole) in H2O (20 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with EtOAc (200 mL). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The solid residue was purified by flash chromatography on silica gel (5-10% EtOAc/CHCl3) to afford a solid (2.5 g, 38%): MS (ES) m/z 253.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-])=O.[CH:14](=O)[CH3:15].[CH2:17](O)[CH3:18]>[Pd]>[CH2:17]([N:1]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])[CH3:18]
Reactant: CC=O
Reactant: CCO
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Product: CCN(CC)c1ccccc1CC(=O)O

Procedure:
2-Diethylaminonphenylacetic acid is prepared by hydrogenation of a suspension of 2-nitrophenylacetic acid (9 g) in ethanol (40 cc) under a pressure of 7 bar for 4 hours at 25° C. in the presence of acetaldehyde (7 cc) and 10% palladium-on-carbon black (1 g). The reaction mixture is filtered, the filtrate is concentrated to dryness under reduced pressssure (2.7 kPa) and the residue is chromatographed on a silica column (0.2-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 125 cc fractions. Fractions 38 to 48 are concentrated to dryness under reduced pressure (2.7 kPa) to give 2-diethylaminophenylacetic acid (1.1 g) in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.C(O)CCC.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH2:24]1>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Clc1nccc(NCCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
To 2,4-dichloropyrimidine (5.0 g, 33.5 mmol), diisoproylethylamine (5.85 ml, 33.5 mmol) in 50 ml of a 1:1 mixture of n-butanol and water is added 3-morpholinopropan-1-amine (4.90 ml, 33.5 mmol). The resulting mixture was stirred for 18 hours at room temperature. The mixture is then concentrated in vacuo, diluted with 30 mL water and extracted with EtOAc (3×50 ml). Combined organic layers are washed with saturated NaHCO3 (2×20 ml) and saturated NaCl (2×20 ml), then dried over magnesium sulfate. The residue is purified over silica (25% EtOAc in Hexanes) to afford 4.5 g (51% yield) of the desired product. 1H NMR (CDCl3, 300 MHz): δ(ppm) 1.83 (q, J=2.0 Hz, 2H), 2.54 (m, 6H), 3.53 (bs, 2H), 3.79 (t, J=4.7 Hz, 4H), 6.24 (d, J=5.67 Hz, 1H), 6.92 (bs, 1H), 7.99 (bs, 1H). MS (ESI, pos. ion) m/z: 257 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([OH:22])=O)=[C:16]([CH3:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:22])=[C:16]([CH3:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccncc1
Reactant: Cc1cc2c(cc1C(=O)O)SCCC2NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: Cc1cc2c(cc1C(=O)Nc1ccncc1)SCCC2NC(=O)OC(C)(C)C
Yield: 67.5 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using 4-(tert-butoxycarbonylamino)-6-methylthiochromane-7-carboxylic acid (1.00 g), 4-aminopyridine (321 mg) and 2-chloro-1-methylpyridinium iodide (949 mg), the objective 4-(tert-butoxycarbonylamino)-6-methyl-N-(4-pyridyl)thiochromane-7-carboxamide (834 mg) was obtained as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:6])[CH3:5].C1COCC1.CO.O[Li].O>O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:20])=[O:2])(=[O:10])=[O:9])=[CH:12][CH:13]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)C(C)(C)NS(=O)(=O)c1ccc(C(C)=O)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
methyl-2-(4-acetylphenylsulfonamido)-2-methylpropanoate (2.55 g, 8.52 mmol) was charged, and dissolved through addition of THF (20 ml), and methanol (20 ml). LiOH.H2O dissolved in H2O (10 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2-3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 2-(4-acetylphenylsulfonamido)-2-methylpropionic acid (2.38 g, 8.35 mmol, 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][C@H:10]([CH2:12][OH:13])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][C@H:10]([CH2:12][O:13][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](COS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (4S)-1-(tert-butyloxycarbonyl)-4-hydroxymethyl-L-proline tert-butyl ester (364 mg, 1.21 mmol) in pyridine (2 mL) cooled to 0° C. was added methanesulfonyl chloride (0.19 mL, 2.42 mmol). The reaction mixture was stirred for 2 hours at ice temperature, diluted with ethyl acetate (100 mL), washed with 1M sodium hydrogencarbonate solution, 1M citric acid, water, saturated brine solution, dried (Na2 SO4), and evaporated. The crude product was purified by flash silica gel chromatography eluting with 20% acetone/hexane; yield 437 mg (95%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl>[CH3:24][S:21]([O:14][CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([C:10]#[N:11])=[C:7]([O:8][CH3:9])[C:2]=1[Cl:1])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C#N)ccc(CCO)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C#N)ccc(CCOS(C)(=O)=O)c1Cl
Reaction time: 2 h

Procedure:
A solution of 2-(2-chloro-4-cyano-3-methoxyphenyl)ethanol (205 mg, 0.969 mmol) DIPEA (0.846 mL, 4.84 mmol) and pyridine (0.078 mL, 0.969 mmol) in DCM (3 mL) was treated dropwise with mesyl chloride (0.110 mL, 1.417 mmol). The reaction was stirred for 2 hours and was then diluted with DCM and washed twice with aq. citric acid, then washed with brine, and dried over sodium sulfate. The residue was purified by flash chromatography (20-50% ethyl acetate/hexanes) to afford the title intermediate.
Reaction SMILES: C(OC1C(Br)=[C:7]([C@H:21]2[C@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:25]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:24]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@@H:23]([CH2:51][O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:22]2)[CH:8]=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:10]=1[Cl:11])C=C.[CH3:61]CCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C.[F-].[K+].[CH3:88][CH2:89][O:90][C:91]([CH3:93])=O>>[Cl:11][C:10]1[C:91]2[O:90][CH2:89][CH:88]([CH3:61])[C:93]=2[C:7]([C@H:21]2[C@H:26]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@@H:25]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:24]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C@@H:23]([CH2:51][O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:22]2)=[CH:8][C:9]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C=CCOc1c(Cl)c(Cc2ccc(CC)cc2)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1Br
Reactant: CCOC(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [F-]
Agent: [K+]
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3C)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
To a solution of the 163 (1.52 g, 1.71 mmol) were added Bu3SnH (3.7 ml, 13.7 mmol) and AIBN (112 mg, 0.68 mmol). After stirring for 20 h at 120° C., aq. 10% KF solution was added to quench the reaction. The residue was dissolved in EtOAc (100 mL), washed with saturated NaHCO3 solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 164 (538 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]#[N:10])[N:3]=1.[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([C:9]#[N:10])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)nc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(Cl)n1
Reaction time: 1 h
Yield: 40 %

Procedure:
2-Chloro-6-cyano-3-methylpyridine (92.0 mg, 0.603 mmol) obtained in Step 2 was dissolved in carbon tetrachloride (4 mL), and the mixture was stirred for 1 hour under reflux after adding N-bromosuccinimide (118 mg, 0.663 mmol) and α,α-azobisisobutyronitrile (9.90 mg, 0.0603 mmol). The mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC to give 3-bromomethyl-2-chloro-6-cyanopyridine (55.8 mg, 40%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.21 (2H, s), 6.72 (1H, d, J=2.0 Hz), 7.26 (1H, s), 7.37-7.47 (4H, m), 7.56 (1H, d, J=2.0 Hz), 8.03 (1H, s), 8.69 (1H, d, J=4.8 Hz) [M+H] Calc'd for C16H11ClN4O, 311. Found, 311.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([Br:18])[CH:6]=2.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20]>ClCCl>[Br:18][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([NH:12][CH2:13][C:14]([OH:16])([CH3:15])[CH3:17])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][O:21][CH2:19][CH3:20])[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Product: CCOCC(=O)Nc1cnc2cc(Br)ccc2c1NCC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (158.19 g, 0.510 mol) in dichloromethane (1.2 L) was cooled to 0° C. Ethoxyacetyl chloride (62.50 g, 0.510 mol) was added dropwise, and then the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration to provide N-[7-bromo-4-(2-hydroxy-2-methylpropylamino)quinolin-3-yl]-2-ethoxyacetamide as a solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:48]([O:50][C:51](=[O:54])[CH2:52][NH2:53])[CH3:49]>CN(C=O)C.O>[CH2:48]([O:50][C:51](=[O:54])[CH2:52][NH:53][C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:18])[CH3:49]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 0.03 h
Yield: 87.5 %

Procedure:
DIPEA (7.825 g, 60.54 mmol) was added to a stirred solution of biphenyl-4-carboxylic acid (4 g, 20.18 mmol) in DMF (40 mL). HOBT (3.27 g, 24.22 mmol) and EDCI.HCl (3.87 mg, 24.22 mmol) were then added at room temperature. After 2 minutes, glycine ethyl ester hydrochloride (3.381 g, 24.22 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 5 g (87.4% yield) of [(biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester. LC-MS purity: 93.4%
Reaction SMILES: O[Li].O.[CH3:4][C@H:5]1[C:13]2[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=2[C@H:7]([O:27]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:6]1.C1COCC1>O>[OH:27][C@H:7]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:13]=2[C@H:5]([CH3:4])[CH2:6]1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reaction time: 1 h
Yield: 99.9 %

Procedure:
LiOH—H2O (0.499 g, 11.9 mmol) was added to a 0° C. solution of tert-butyl 4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (2.30 g, 4.76 mmol) in 2:1 THF:H2O (40 mL) The reaction mixture was warmed to room temperature and stirred for 1 hour. The THF was removed by rotary evaporation, saturated NaHCO3 was added, and the mixture was extracted with ethyl acetate. The combined extracts were washed (1×) with saturated NaHCO3, dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.59 g, 100.0% yield) as a yellow foam. HPLC after workup just product>98 area % pure. LC/MS (APCI+) m/z 335 [M+H]+. The tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate was prepared using an analogous method.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[C:10](=O)(O)O.[Na].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CCOC(C)=O.O>[CH3:10][O:8][C:7](=[O:9])[C@@H:2]([NH:1][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)O
Reactant: CSCC[C@H](N)C(=O)O
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1

Procedure:
L-methionine (3.70 g, 18.5 mmol) was dissolved in a biphasic mixture of EtOAc (75 mL) and water (75 mL). This was cooled in ice and sodium hydrogen bicarbonate (7.78 g, 5 equiv) and benzyl chloroformate (2.98 mL, 1.1 equiv) were added. This was stirred in ice for one h and then at rt for a further eighteen h before the mixture was allowed to partition. The organic phase was washed sequentially with 1M hydrochloric acid, saturated aqueous sodium hydrogen bicarbonate and brine before being dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil, 5.40 g, 98%.