Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1C(=O)[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH2:3]1.[CH3:19][O:20][CH:21](OC)[O:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:19][O:20][C:21]1([O:22][CH3:23])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH2:3][CH:2]1[F:1]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC1(OC)CCN(c2ccc([N+](=O)[O-])cc2F)CC1F
Temperature: 45 °C
Yield: 78 %

Procedure:
The mixture of 4-(3-fluoro-4-oxo-piperidin-1-yl)-3-fluoronitrobenzene (65 mmol), trimethylorthoformate (130 mmol), p-toluene-sulphonic acid monohydrate (67 mmol) in methanol was heated at 45° C. for 24 hours. Solvent was removed and residual mass was taken into ethyl acetate and saturated sodium bicarbonate solution mixture. The organic layer was dried and removal of the solvent afforded title compound as a solid in 78% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[CH2:30]([NH2:33])[C:31]#[CH:32].ClCCl>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14]([NH:33][CH2:30][C:31]#[CH:32])=[O:25])[CH2:7]1
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: C#CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 79.1 %

Procedure:
Example 57 was prepared in an analogous manner to Example 43 from Intermediate 13 (0.1 g) and propargylamine (0.014 g) using dichloromethane and triethylamine at a temperature of 22° C. to yield the title compound (0.064 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2
Reactant: Nc1ccc2ncccc2c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc2ncccc2c1
Temperature: 110 °C
Yield: 85.7 %

Procedure:
A mixture of 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (164.5 mg, 0.5 mmol), 6-aminoquinoline (72.2 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 0.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide (DMF) and ether to give 189 mg (85%) of yellow solid. MS (ESI) m/z 442.0 (M+H)+1
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)([O:16][CH3:17])[CH2:5][CH2:6][C:7]1([CH3:15])[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8]1.[C:25]1([C:31]#[C:32][CH2:33]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][CH2:3][C:4]([O:16][CH3:17])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:33][C:32]#[C:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)[CH2:5][CH2:6][C:7]1([CH3:15])[O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12]1
Reactant: BrCC#Cc1ccccc1
Reactant: COCC(CCC1(C)OCC(C)(C)CO1)(OC)c1cccc(O)c1
Product: COCC(CCC1(C)OCC(C)(C)CO1)(OC)c1cccc(OCC#Cc2ccccc2)c1
Yield: 85 %

Procedure:
Using the procedure described in Example 12, 2-(3-hydroxyphenyl)-2-methoxy-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)but-1-yl methyl ether was reacted with 3-phenylprop-2-ynyl bromide to give 2-methoxy-2-[3-(3-phenylprop-2-ynyloxy)phenyl]-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)but-1-yl methyl ether in 85% yield, as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=3[F:21])[N:9]=[CH:10][C:3]=12.C(=O)([O-])N.[CH:26]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])[CH3:27].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH:26]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([O:38][C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=4[F:21])[N:9]=[CH:10][C:3]=23)[CH2:36][CH2:37]1)=[O:31])([CH3:28])[CH3:27]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: NC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 12 °C
Yield: 74.4 %

Procedure:
Toluene (1.6 L) was transferred to a 4 L jacketed reaction vessel fitted with a mechanical stirrer, nitrogen inlet and a temperature probe. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) (97.0 g, 0.297 mol) was added with stirring into the reaction vessel under nitrogen, and a slurry was obtained. The carbamate, 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (5) (66.57 g, 0.356 mol), was added at room temperature. The reactor was cooled to 12° C. and sodium tert-butoxide (37.09 g, 0.386 mol) was added with stirring. The internal temperature gradually increased to 34° C. due to an exotherm. Then the internal temperature was brought down to 23-25° C. The reaction mixture became a thick slurry and was stirred at room temperature for 2.5 h. The precipitate from the reaction mixture was filtered, washed with toluene (250 mL) followed by water (3×500 mL), and vacuum dried overnight at room temperature. The dried solid product was slurried in EtOH (500 mL) at room temperature, filtered, and washed with water (2.5 L) until the filtrate was neutral. The washed solid product was dissolved in refluxing EtOH (1.3 L), and the resulting clear solution was gradually cooled to room temperature. The product (6) crystallized out and was isolated by filtration and dried overnight in a vacuum oven at 40° C., 20 torr to provide 105.5 g of product (6) (74%). HPLC analysis, >99% (purity, by peak area). 1H NMR (Bruker 400 MHz, CDCl3) δ 8.62 (s, 1H, Ar—H), 8.32 (s, 1H, Ar—H), 7.93 (m, 3H, Ar—H), 5.62 (m, 1H, —O—CH—), 4.95 (m, 1H, CH3—CH—CH3), 3.91 (m, 2H, —CH2—), 3.37 (m, 2H, —CH2—), 3.12 (s, 3H, —SO2CH3), 2.09 (m, 2H, —CH2—), 1.87 (m, 2H, —CH2—), 1.27 (d, 6H, J=8 Hz, CH3—CH—CH3); mass spec. (electrospray) m/z 478 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:24][CH3:25])[C:9]3[C:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)=[CH:13][N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1.[CH2:26]([NH2:28])[CH3:27]>>[CH2:24]([N:8]1[C:9]2[C:14]([C:15]3[CH:22]=[CH:21][CH:20]=[C:17]([CH2:18][NH:28][CH2:26][CH3:27])[CH:16]=3)=[CH:13][N:12]=[CH:11][C:10]=2[N:23]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH3:25]
Reactant: CCn1c(-c2nonc2N)nc2cncc(-c3cccc(C=O)c3)c21
Reactant: CCN
Product: CCNCc1cccc(-c2cncc3nc(-c4nonc4N)n(CC)c23)c1

Procedure:
The product of Step 1 was converted into the title compound by reaction with ethylamine (1M in THF) according to the general method of Example 149. MS (ES+) m/e 364 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].[Br:8][C:9]1[CH:16]=[CH:15]C(CBr)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:8][C:9]1[CH:16]=[CH:15][C:5]([CH2:4][CH2:3][C:2](=[O:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 2,4-pentanedione (200 mg, 206 μL, 2 mmol), the 4-bromobenzyl bromide (2 mmol), and anhydrous potassium carbonate (276 mg, 2 mmol) in methanol (10 mL) was heated at reflux temperature for 16 h. The mixture was then cooled to room temperature, methanol was removed under reduced pressure, and the resulting residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (3×10 mL). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, and then the solvent was removed under pressure. The resulting oil was chromatographed on a silica gel column using hexanes-ethyl acetate as mobile phase to give 4-(4-bromophenyl)-2-butanone as a clear liquid (302 mg, 67%): Rf=0.38 (hexanes-ethyl acetate 3:1 v/v); 1H NMR (400 MHz, CDCl3): δ 2.15 (s, 3H), 2.75 (t, J=7.2 Hz, 2H), 2.86 (t, J=7.2 Hz, 2H), 7.07 (d, J=8 Hz, 2H), 7.40 (d, J=8.4 Hz, 21; 13C NMR (100 MHz, CDCl3): δ 29.2, 30.2, 44.9, 120.0, 130.2, 131.7, 140.2, 207.4; HRMS (ESI) Calcd. for C10H11BrONa: 248.9891 [M+Na+]. Found: 248.9880.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].[OH-].[Na+]>C(O)C.O>[CH:1](=[N:10]/[OH:11])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O/N=C\c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a suspension of benzaldehyde (5.30 g, 55 mmol) and hydroxylamine hydrochloride (3.82 g, 55 mmol) in ethanol (4 mL) and water (12 mL) was added ice (23 g). Then a solution of sodium hydroxide (5.0 g, 125 mmol) in water (6 mL) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (5.31 g, 88%) which was obtained as a colourless liquid. MS m/e (EI): 121.0 [M].
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:35])[N:17]([C:21]3[C:22]([CH3:34])=[CH:23][C:24]([F:33])=[C:25]([CH:32]=3)[C:26]([NH:28][CH:29]3[CH2:31][CH2:30]3)=[O:27])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH3:36][NH2:37].[I-].[K+]>O.O1CCOCC1>[CH:29]1([NH:28][C:26](=[O:27])[C:25]2[CH:32]=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:13][CH2:12]4)[C:16]3=[O:35])[C:22]([CH3:34])=[CH:23][C:24]=2[F:33])[CH2:31][CH2:30]1
Reactant: Cc1cc(F)c(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Reactant: CN
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)c(F)cc3C)c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-2-fluoro-4-methylbenzamide (Example 318h, 100 mg) and methylamine, 40% by wt solution in water (0.1 mL) in dioxane (1 mL) was added potassium iodide (33.4 mg). The reaction mixture was stirred at room temperature overnight, then heated at 40° C. overnight. The reaction was heated at 50° C. for 48 h. Purification by preparative HPLC (Phenomenex Gemini, eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia, followed by Xbridge column eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the title compound as a solid (17 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=O)[CH2:30][C:31]([CH3:36])([CH3:35])[O:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CCOCC>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[CH:30][C:31]([CH3:36])([CH3:35])[O:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)CC(=O)c2ccc(OCc3ccccc3)cc2O1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1(C)C=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCc3ccccc3)cc2O1
Reaction time: 2 h

Procedure:
n-Butyl-lithium (142 ml of a 2.4 M solution) was added under dry nitrogen to a solution of 4-bromobenzotrifluoride (76.5 g) in dry ether at -50° C. The mixture was left to stir for 2 hours. 7-Benzyloxy-2,2-dimethylchroman-4-one (64g) in dry ether was added dropwise. Water was added and the ether layer washed with 5N.HCl (2×100 ml), and dried (MgSO4). Removal of the solvent under reduced pressure gave an oil (84 g) which was chromatographed on alumina. Elution with petrol-ether (1:1) gave the title compound (52 g).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
1.4 g (2.69 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-benzyloxyphenyl)methyl]-hexanoic acid in 2.9 ml of DMF are stirred, at RT for 18 h, together with 1.87 g (12.4 mmol) of tert-butyldimethylchlorosilane and 1.5 g (22 mmol) of imidazole. The reaction mixture is then poured onto ice water, and this mixture is extracted with 3 portions of ethyl acetate; the combined organic phases are washed with 10% citric acid solution, water and saline, dried with sodium sulfate and evaporated. An oil is obtained. This is followed by hydrolysis of the silyl ester function of the oil, at RT, using 2.2 g of potassium carbonate in 63 ml of methanol/water/THF,3:1:1, and partial evaporation at RT. The aqueous residue is poured onto 10% citric acid solution and ice, and this mixture is extracted 3 times with ethyl acetate; the organic phases are washed twice with water and saline, dried with sodium sulfate and evaporated. Column chromatography (SiO2, D) of the crude product yields the title compound: TLC Rf (D)=0.17; tRet (I)=33.7 min; FAB-NS (M+H)+ =634.
Reaction SMILES: C1CCCCC1.S(=O)(=O)(O)O.O=O.[N+:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:23])([O-:16])=[O:15].[N+:24](C1CCCCC1)([O-:26])=[O:25]>C(Cl)(Cl)(Cl)Cl>[N+:24]([O-:26])([O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N+:14]([O-:16])=[O:15])=[O:25]
Reactant: O=[N+]([O-])C1CCCCC1O
Reactant: O=[N+]([O-])C1CCCCC1
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: O=[N+]([O-])OC1CCCCC1[N+](=O)[O-]
Yield: 30 %

Procedure:
A solution of 4.4 grams (50 mmoles) of cyclohexane in 50 milliliters of carbon tetrachloride containing 1 milliliter of concentrated sulfuric acid was treated with 6.9 grams of N2O4 and 21 grams of oxygen at about 5°C. Analysis of the isolated product (7.3 grams) showed it consisted of a mixture of 2-nitrocyclohexyl nitrate (30 percent yield), 2-nitrocyclohexanol, nitrocyclohexane and carboxylic acids.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.P(Br)(Br)([Br:27])=O.C1C=CC2N=CNC(=O)C=2C=1>C1(C)C=CC=CC=1>[Br:27][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:16]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc2ccccc12
Reactant: O=P(Br)(Br)Br
Agent: O=c1[nH]cnc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Brc1nc(-c2ccccc2)nc2ccccc12
Yield: 46.3 %

Procedure:
Into a mixture of 5 g of 2-phenylquinazolin-4(3H)-one and 1.82 g of triethylamine in 100 ml of toluene was added a solution of 25.8 g of phosphorus oxybromide in 50 ml of toluene. The mixture was warmed slightly and the insoluble quinazolinone dissolved slowly, with a new solid appearing. The reaction mixture was heated at 80°-85° for approximately 24 hours. The reaction mixture was cooled and the solid which separated was collected on a filter. The collected solid was dissolved in chloroform, was washed twice with 100-ml portions of water and the washed solution dried over magnesium sulfate. The solution was concentrated to dryness to leave a light orange solid, m.p. 131°-132°. This solid was recrystallized from cyclohexane to give 2.97 g of light yellow 4-bromo-2-phenylquinazoline, m.p. 131.5°-132.5°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][NH:8]1.ClC1C=C(Cl)C=C(Cl)C=1[O:47][S:48](=O)(=[O:50])[NH2:49].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][N:8]1[S:48]([NH2:49])(=[O:50])=[O:47]
Reactant: NS(=O)(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Yield: 43.8 %

Procedure:
A solution of 567 mg (1.09 mmol) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, 302 mg (1.09 mmol) sulfamic acid 2,4,6-trichloro-phenyl ester [Hedayatullah, M. & Hugueny, J. Phosphorus, Sulfur Silicon Relat. Elem. (1991), 61(1–2), 19–25.] and 0.15 ml triethylamine in 2 ml CH2Cl2 was heated for 1 h at reflux, evaporated and purified by flash column chromatography on silica gel with hexane/EtOAc (9:1 to 1:1) to give 286 mg (44%) (2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-sulfonic acid amide. [Hedayatullah, M. & Hugueny, J. Phosphorus Sulfur (1985), 25(1), 33-8.] MS: 621 (M+Na+).
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].O1CCCC1.[C:15]([O-])(=[O:19])[CH:16]([CH3:18])[CH3:17].[Na+].Cl>O>[C:15]([NH:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)[O-]
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)N[C@@H](CS)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 35.2 g (0.20 mol) of L-cysteine hydrochloride monohydrate in 100 ml of a mixture of 80% of tetrahydrofuran (THF) and 20% of water was stirred under nitrogen at room temperature and treated with 44.0 g (0.40 mol) of sodium isobutyrate. The reaction mixture (white slurry) was cooled to 0°-5° C. and, under nitrogen, 35 ml (0.21 mol) of isobutyryl anhydride was added dropwise. The resulting mobile suspension was stirred for 6h at room temperature, allowed to stand overnight, and finally heated under reflux for 4 h. The reaction mixture was cooled on an ice bath and 18 ml of concentrated hydrogen chloride was added. The organic phase was evaporated to give a colourless oil. The oil was washed with hexane and thereafter treated with ether to give 12.9 g of the title compound as a white solid, mp 103°-104° C. (recrystallized from butyl acetate), [α]D25 =+23.4° C. (c 5.0, H2O, pH=7.0), 1H-NMR (CDCl3): δ 1.2 (6H, d, CH3), 1.4 (1H, t, SH), 2.5 (1H, sept, CH), 3.1 (2H, m, CH2), 4.9 (1H, dt, NCH), 6.7 (1H, d, NH), 10.6 (1H, s, OH). 13C-NMR (CDCl3): δ 19, 19.5; 26.5; 36; 54, 172, 178. ms: 335 (M+ +2TMS, after silylation).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH:6]=[CH:5]2.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.C(OCC)(=O)C.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>[CH3:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[CH:3]=2)[N:8]=1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3ccc(C#N)cc3)ccc2n1
Temperature: 25 °C

Procedure:
The product from Example 42D (160 mg, 0.5 mmol), 4-cyanophenylboronic acid (0.75 mmol), and dichlorobis(triphenylphosphine)palladium (II) (35.1 mg, 0.05 mmol) were combined in isopropyl alcohol (5.0 mL) and 0.2 M K3PO4 aq. solution (5.0 mL, 1.0 mmol) and heated at 60° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (20 mL). The organic phase was separated, washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with one equivalent of L-tartaric acid in IPA:ethanol to give the tartrate salt. mp 164° C.; MS (ESI) 342 (M+H)+; 1H NMR (DMSO-d6) δ 8.40 (1H, d), 8.38 (1H, d), 8.12 (1H, d), 8.06 (1H, d), 8.04 (2H, d), 7.98 (2H, d), 7.58 (1H, d), 4.05 (2H, s), 3.63 (1H, m), 3.50 (1H, m), 3.33 (2H, t), 3.15 (2H, m), 2.88 (1H, m), 2.09 (1H, m), 1.86 (2H, m), 1.55 (1H, m), 1.29 (3H, d).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:32]=[CH:31][C:10]([C:11]([NH:13]/[C:14](/[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:15]\[C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C.C1COCC1>[CH:22]1([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH:14]([NH:13][C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)=[CH:32][CH:31]=3)[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:17][CH:18]=2)[CH2:23][CH2:24]1
Reactant: O=C(NCCO)/C(=C/c1ccc(C2CC2)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccc(C2CC2)cc1)C(=O)NCCO)c1ccc(OCCC2CC2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 53.7 %

Procedure:
To an ethanol:THF (4:1, V/V, 7.5 mL) solution of 4-(2-cyclopropylethoxy)-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (165 mg, 0.380 mmol) prepared in Example 1 (1d) was added tris(triphenylphosphine)rhodium(I) chloride (71 mg, 0.076 mmol). The mixture was stirred under a hydrogen atmosphere (rubber balloon) at 60° C. for 5 hours. The reaction solution was cooled to room temperature, and the solvent was evaporated. The residue was purified by alumina column chromatography (ethyl acetate to ethyl acetate:methanol, 10:1, V/V) to give 89 mg of the title compound (white powder, yield: 54%).