Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C(Cl)=O)C(=CC=1)C(Cl)=O.ClC1C=C(C#N)C(=CC=1)C#N.[Cl:25][C:26]1[CH:27]=[C:28]([C:35]([OH:37])=[O:36])[C:29](=[CH:33][CH:34]=1)[C:30]([OH:32])=O>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:35](=[O:36])[O:37][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)O
Agent: N#Cc1ccc(Cl)cc1C#N
Agent: O=C(Cl)c1ccc(Cl)cc1C(=O)Cl
Product: O=C1OC(=O)c2cc(Cl)ccc21

Procedure:
In a conventional acidic hydrolysis, the 4-chlorophthaloyl chloride or 4-chlorophthalonitrile of Examples 7 or 8 is hydrolyzed to 4-chlorophthalic acid which, upon dehydration at over 180°-200° C., will afford a high yield of 4-chlorophthalic anhydride.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][N:28]1[C:33]2[CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:37][C:32]=2[O:31][CH2:30][C:29]1=[O:47]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[CH:37][C:32]5[O:31][CH2:30][C:29](=[O:47])[N:28]([CH3:27])[C:33]=5[CH:34]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1C(=O)COc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccc4c(c3)N(C)C(=O)CO4)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 129, Step 4 starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one. LCMS (M+H)+: m/z=500.2.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[C:8]3=[C:7]3[CH:20]=[C:21]([CH3:23])[CH:22]=[C:5]([C:6]=23)[C:4]1(O)[CH2:24][CH2:25][CH3:26])[CH3:2]>C(O)C.[Zn].[Hg](Cl)Cl>[CH2:1]([N:3]1[C@@H:11]2[C:6]3=[C:7]([CH:20]=[C:21]([CH3:23])[CH:22]=[C:5]3[C@H:4]1[CH2:24][CH2:25][CH3:26])[C:8]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH2:10]2)[CH3:2]
Reactant: CCCC1(O)c2cc(C)cc3c2c(cc2ccc(OC)c(OC)c23)N1CC
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: CCO
Product: CCC[C@@H]1c2cc(C)cc3c2[C@H](Cc2ccc(OC)c(OC)c2-3)N1CC
Temperature: 25 °C

Procedure:
A suspension of 100 g (0.273M) of 5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-2-methyl-4-n-propyl-dibenz[cd,f]indole in 2000 ml ethanol is added with stirring to a suspension of 322 g (4.928M) of zinc dust and 74.3 g (0.273M) of mercury(II) chloride in 2000 ml distilled water. The reaction mixture is refluxed, 450 ml of 18% hydrochloric acid are added dropwise over a period of 15 minutes and the mixture is refluxed overnight with stirring. The mixture is then cooled to room temperature, filtered and the zinc amalgam is washed with 500 ml methylene chloride. The filtrate is made alkaline with 1 liter of concentrated NH4OH and extracted three times with methylene chloride (700 ml each time). The combined organic phases are washed with water, dried and evaporated. The resultant oil is chromatographed on silica gel using methylene chloride with 2% methanol to give the title compound as an oil.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([O:17][C@H:18]1[C@@H:23]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:22][C@H:21]2[C@H:30]3[C@H:40]([CH2:41][CH2:42][C@:19]12[CH3:20])[C@:38]1([CH3:39])[C@H:33]([CH2:34][CH2:35][C@@H:36]([OH:43])[CH2:37]1)[CH2:32][CH2:31]3)(=[O:16])[CH3:15]>CC(C)=O>[C:14]([O:17][C@H:18]1[C@@H:23]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:22][C@H:21]2[C@H:30]3[C@H:40]([CH2:41][CH2:42][C@:19]12[CH3:20])[C@:38]1([CH3:39])[C@H:33]([CH2:34][CH2:35][C:36](=[O:43])[CH2:37]1)[CH2:32][CH2:31]3)(=[O:16])[CH3:15]
Reactant: CC(=O)O[C@H]1[C@@H](N2CCCCC2)C[C@H]2[C@@H]3CC[C@H]4CC[C@@H](O)C[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(=O)O[C@H]1[C@@H](N2CCCCC2)C[C@H]2[C@@H]3CC[C@H]4CCC(=O)C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 5 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
Jones reagent (21.0 ml; 8N) was added dropwise to a stirred suspension of 16β-(1-piperidinyl)-5α-androstane-2β,17β-diol 17-acetate (14.0 g) in acetone (250 ml), cooled to approx. 5° C. in an ice-bath. When the addition was complete, the cooling bath was removed and stirring was continued for 3 h. Saturated sodium carbonate solution (100 ml) was added to give pH approx. 9 and the product was extracted into dichloromethane (150 ml). The organic layer was separated, washed neutral with water (3×150 ml) and dried (MgSO4). The solution was concentrated while ether was added to afford 17β-acetyloxy-16β-(1-piperidinyl)-5α-androstan-2-one (12.2 g) m.p. 165°-167° C.; [α]D +44.6° (c 0.45 in CHCl3).
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([Br:15])[N:9]=1.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>>[Br:15][C:10]1[N:9]=[C:8]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][N:18]=2)[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: Cc1cc(Br)nc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cc1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium tert-butoxide (5.87 g, 61.1 mmol) and 1,1′-bis(di-tert-butylphsophino)ferrocene palladium dichloride (0.91 g, 1.4 mmol) were added to a solution of 2,6-dibromo-4-methyl pyridine (13.9 g, 55.5 mmol) and 2-amino-4-trifluoromethyl pyridine (9.0 g, 55.5 mmol) in nitrogen sparged dioxane (180 mL). The slurry was evacuated and refilled with nitrogen. The mixture was stirred at 25° C. for 15 minutes and then heated to 75° C. for 12 hours. The reaction mixture was cooled to 25° C., water (20 mL) was added, and the mixture was extracted with EtOAc (2×200 mL). The combined extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amine as a white solid. MS ESI calc'd. for C12H10BrF3N3 [M+H]+ 332 and 334. found 332 and 334. 1H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.18 (d, J=6.0 Hz, 1H), 7.00 (s, 1H), 2.25 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([Br:11])=[N:7][NH:6][C:5]1=[O:12])[CH:2]=[CH2:3].[C:13]([NH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:15])[CH3:14].N1C=CC=CC=1>CN(C=O)C.C([O-])(O)=O.[Na+].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([Br:11])=[N:7][N:6]([C:21]2[CH:22]=[C:17]([NH:16][C:13](=[O:15])[CH3:14])[CH:18]=[CH:19][CH:20]=2)[C:5]1=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)[nH]nc(Br)c1=O
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CCn1c(=O)c(Br)nn(-c2cccc(NC(C)=O)c2)c1=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 46.2 %

Procedure:
According to Scheme 3 Step 2: A mixture of compound 6(A) (1.10 g, 4.74 mmol), 3-acetamidophenylboronic acid (1.20 g, 6.64 mmol), copper acetate (258 mg, 1.42 mmol) and pyridine (229 μL, 2.84 mmol) in DMF (30 mL) was stirred at 65° C. during 15 h under room atmosphere. The mixture was diluted with 50 mL of a saturated solution of NaHCO3 and the aqueous layer was extracted twice with 60 mL of DCM. The organic layers were combined dried over MgSO4, filtered filtrated and concentrated under reduce pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 10 g SiO2) (Eluant: CH2Cl2/MeOH 98/2) to afford N-(3-(4-allyl-6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 6(B) (800 mg, 46%) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:20][N:21]([CH3:24])[CH:22]=[O:23].C(N(CC)CC)C.CN(C)C(Cl)=O>O>[CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH:17][C:22]([N:21]([CH3:24])[CH3:20])=[O:23])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CN(C)C=O
Reactant: CC1Cc2cc(COc3ccc(N)cc3)ccc2O1
Agent: CN(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1Cc2cc(COc3ccc(NC(=O)N(C)C)cc3)ccc2O1
Temperature: 25 °C

Procedure:
6.5 g of 4-(2,3-dihydro-2-methyl-5-benzofuranylmethyloxy)aniline was dissolved into 70 ml of N,N-dimethylformamide, and 2.8 g of triethylamine was added thereto. 3.8 g of N,N-dimethylcarbamoyl chloride was slowly added dropwise thereto. After the mixture was stirred at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (2/1) as a developer to obtain 5.8 g of Compound No. 41 shown in Table 2.
Reaction SMILES: C1(C(OC)=O)CCCCC=1.[F:11][C:12]1([F:22])[CH:18]2[CH:13]1[CH2:14][CH2:15][CH:16]([C:19]([O-])=[O:20])[CH2:17]2>>[F:11][C:12]1([F:22])[CH:18]2[CH:13]1[CH2:14][CH2:15][CH:16]([CH2:19][OH:20])[CH2:17]2
Reactant: O=C([O-])C1CCC2C(C1)C2(F)F
Agent: COC(=O)C1=CCCCC1
Product: OCC1CCC2C(C1)C2(F)F

Procedure:
Following the procedure as described in Example 342 Step 1 and making non-critical variations to replace methyl cyclohex-1-enecarboxylate with 7,7-difluorobicyclo[4.1.0]-heptane-3-carboxylate, the title compound was obtained as a colorless liquid (0.30 g, 70%): 1H NMR (300 MHz, CDCl3) δ 3.50-3.23 (m, 2H), 2.50-2.25 (m, 1H), 2.15-1.76 (m, 2H), 1.74-0.96 (m, 5H), 0.96-0.54 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.B(F)(F)F.CCOCC>>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]([OH:9])[CH:7]=[CH:6][C:5]=1[C:19](=[O:20])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1
Reactant: Cc1c(O)cccc1O
Reactant: COc1ccc(CC(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: COc1ccc(CC(=O)c2ccc(O)c(C)c2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methyl resorcinol (1 eq) and p-methoxy phenyl acetic acid (1 eq) in boron trifluoride diethyl etherate (8 eq) was refluxed for 3½ h, whilst stirring, under nitrogen. The brown solution was allowed to cool to room temperature, quenched with NaOAc solution (10% w/v) and left to stand overnight. The resultant precipitate was filtered, washed with water and dried to give 1-(2,4-dihydroxy-3-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)=[O:4].[OH-].[Na+]>CO>[F:28][C:26]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:19]([CH3:20])([CH3:21])[CH2:18][C:17]([OH:35])([C:31]([F:33])([F:32])[F:34])[CH2:16][NH:15][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[N:6]3)[CH:27]=1
Reactant: COC(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C(=O)O)ccc12)C(F)(F)F
Reaction time: 2.5 h

Procedure:
A solution that consists of 60 mg (0.12 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylic acid methyl ester in 10 ml of methanol is mixed with 0.5 ml (0.5 mmol) of 1N sodium hydroxide solution. After 2.5 hours, the solvent is removed in a vacuum, and the residue is purified on silica gel with dichloromethane-methanol (6-25%). 47 mg (82% of theory) is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[C:17]1([S:23]([NH:26][C@@H:27]([CH2:35][NH2:36])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CCOC(C)=O.CC#N>[C:31]([O:30][C:28](=[O:29])[C@@H:27]([NH:26][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH2:35][NH:36][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:15][CH:14]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)c1ccc(OCCCCCl)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCCCCl)cc1)NS(=O)(=O)c1ccccc1

Procedure:
A stirring solution of 24-3 (250 mg, 1.1 mmol), 19-2a (368 mg, 1.1 mmol), NMM (442 mg, 4.4 mmol), and CH3CN (5 mL) at ambient temperature was treated with BOP (483 mg, 1.1 mmol). After 20 h the reaction mixture was diluted with EtOAc and then washed with H2O, sat. NaHCO3, 10% KHSO4 and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes) gave 24-4 as a white solid. TLC Rf =0.46 (silica, 50% EtOAc/hexanes);
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:28])[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:13]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:12]=2[O:11]1>C(#N)C>[Br:1][C:23]1[C:24]([CH3:26])=[CH:25][C:12]2[O:11][C:10]([CH3:28])([CH3:9])[CH:14]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[C:13]=2[C:22]=1[CH3:27]
Reactant: Cc1ccc(C2c3c(C)cc(C)cc3OC2(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1ccc(C2c3c(cc(C)c(Br)c3C)OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.7 %

Procedure:
N-bromosuccinimide (2.1 g, 11.6 mmol) was added to a solution of 2,2,4,6-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran (3.1 g, 11.6 mmol) in acetonitrile (30 ml) with ice cooling and the mixture was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated under reduced pressure. After the remaining solids were removed with filtration, the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (hexane) to obtain 2.67 g (yield 67%) of the title compound via recrystallization (methanol). mp. 116–118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(#N)C>[CH2:16]([O:15][C:13](=[O:14])[NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[Cl:1])[CH3:17]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: CCOC(=O)Cl
Solvent: CC#N
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Yield: 100 %

Procedure:
A suspension of MgO (2.0 g), 2-chloro-4-nitroaniline (3.768 g, 21.83 mmol) and ethyl chloroformate (5 mL) in acetonitrile (25 mL) was heated to reflux temperature for 4 hours followed by addition of more ethyl chloroformate (4 mL). The heating was continued until full conversion (20 hours) then the reaction mixture was filtered via a plug of SiO2 (5 g) with ethyl acetate as an eluent. Evaporation in vacuo (50° C.) gave 5.8 g (100% yield) of crude title compound which was used in the next step without further purification. LC/MS (m/z) 245 ([M+H]+); RT=2.95, (UV, ELSD) 96%, 98.5%. 1H NMR (DMSO-d6): 1.27 (t, 3H), 4.19 (q, 2H), 8.06 (d, 1H), 8.19 (dd, 1H), 8.30 (d, 1H), 9.49 (s, NH).
Reaction SMILES: CN1CCOCC1.C(Cl)(=O)OCC(C)C.[C:16]([NH:23][C@H:24]([C:33](O)=[O:34])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH4-].[Na+]>C(COC)OC.O>[C:19]([O:18][C:16]([NH:23][C@H:24]([CH2:33][OH:34])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](CO)CCc1ccccc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
N-Methylmorpholine (7.2 g, 72 mmol) and isobutyl chlorocarbonate (9.8 g, 72 mmol) were added to a solution of Boc-L-homophenylalanine (20 g, 72 mmol) in dimethoxyethane (100 mL) under ice-cold conditions. After one hour stirring, the reaction solution was filtered, and the filtrate was cooled in an ice bath. Thereafter, an aqueous solution (10 mL) of sodium borohydride (4.1 g, 107 mmol) was added thereto, followed by further addition of water (300 mL). The resulting precipitate was collected by filtration and washed with water and methanol to yield N-(tert-butoxycarbonyl)-L-homophenylalaninol (15 g, 79%) as a colorless crystal.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([O:37][CH2:38][C:39]([F:42])([F:41])[F:40])[CH:28]=4)[CH:24]=[C:23]([C:43]([F:46])([F:45])[F:44])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:42][C:39]([F:40])([F:41])[CH2:38][O:37][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:43]([F:45])([F:46])[F:44])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.9 %

Procedure:
To a cooled and stirred solution of 3-(4-{4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidin-2-yl}-pyridin-2-yl)-benzenesulfonic acid tert-butylamide (0.21 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification by crystallization (diethyl ether) yielded the title compound as an off-white solid (0.15 g, 77%). MS (ISP) 623.2 [(M+H)+]; mp 211° C.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10](=[S:12])[NH2:11])=O)(C)(C)C.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=O)[CH3:21]>>[C:15]1([C:20]2[N:11]3[CH:6]=[N:8][CH:9]=[C:10]3[S:12][CH:21]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1
Reactant: CC(=O)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)NCC(N)=S
Product: c1ccc(-c2csc3cncn23)cc1
Yield: 66 %

Procedure:
The same procedure as in Preparation 10 was repeated except that 1.9 g of (N-t-butoxycarbonylamino) acetothioamide and 2.49 g of 2'-bromoacetophenone were used, thereby obtaining 1.32 g of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH2:12][C:6]2=[N:5][N:4]=1.CS([O-])(=O)=O.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>CS(C)=O.C(Cl)Cl>[CH2:30]([N:32]([CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH2:12][C:6]2=[N:5][N:4]=1)[CH2:33][CH3:34])[CH3:31]
Reactant: O=C1Cc2nnc(CO)n2-c2ccc(Cl)cc2N1c1ccccc1
Reactant: CCNCC
Agent: CS(=O)(=O)[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2
Reaction time: 2 h

Procedure:
3.35 g of 1-(Hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one, methanesulfonate in 15 ml dimethylsulfoxide at 0° is added dropwise with stirring to 3 ml of diethylamine in 10 ml dimethylsulfoxide. The reaction is stirred at 20° for 2 hours, diluted with methylene chloride, washed with water and then saturated aqueous sodium chloride. After drying, the solvent is evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[OH:61][CH2:62][CH2:63][C:64]1([OH:68])[CH2:67][NH:66][CH2:65]1>CN(C=O)C.C(OCC)(=O)C.O>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:66]2[CH2:67][C:64]([CH2:63][CH2:62][OH:61])([OH:68])[CH2:65]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: OCCC1(O)CNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(CCO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
Palladium hydroxide (100 mg) was suspended in a solution of 1-(diphenylmethyl)-3-(2-hydroxyethyl)azetidin-3-ol (228 mg, 0.80 mmol) in methanol (15 mL), and the mixture was subjected to an atmosphere of hydrogen at 50 psi for 4 h. The catalyst was then removed by filtration though celite, and the filtrate was concentrated in vacuo to provide 3-(2-hydroxyethyl)azetidin-3-ol. This material was used in the subsequent reaction without purification. To a solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (314 mg, 0.80 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, in DMF (4 mL) was added PyBOP (416 mg, 0.80 mmol) and triethylamine (223 μL, 1.6 mmol). Finally, the unpurified 3-(2-hydroxyethyl)azetidin-3-ol was added, and the resulting mixture was stirred at rt for 16 h. Water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted with once more with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography, eluting with ethyl acetate, to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxyethyl)azetidin-3-ol as a colorless oil (303 mg, 0.62 mmol, 78% yield). 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.39 (dd, 1H), 7.32 (m, 1H), 7.13 (m, 1H), 6.81 (m, 1H), 6.60 (m, 1H), 4.37 (br s, 1H), 4.28 (br m, 4H), 3.94 (br s, 2H), 2.19 (br s, 1H), 2.02 (m, 2H); MS (EI) for C18H16F3IN2O3: 491 (M-H).
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[C:17]([O:18]CC2C=CC=CC=2)=[C:16]([CH2:26][O:27][CH3:28])[C:15]([C:29]([N:31]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH3:32])=[O:30])=[CH:14][N:13]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:31]([CH3:32])[C:29]([C:15]2[C:16]([CH2:26][O:27][CH3:28])=[C:17]([OH:18])[C:12]([C:10]([NH:9][OH:8])=[O:11])=[N:13][CH:14]=2)=[O:30])=[CH:39][CH:38]=1
Reactant: COCc1c(C(=O)N(C)Cc2ccc(F)cc2)cnc(C(=O)NOCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCc1c(C(=O)N(C)Cc2ccc(F)cc2)cnc(C(=O)NO)c1O
Yield: 59.8 %

Procedure:
Compound 12g (0.100 g, 0.184 mmol, 1 eq) and 10% Pd/C (5 mg) catalyst were stirred in methanol (4.0 mL) under a hydrogen atmosphere for 1 hour. The catalyst was filtered and the reaction mixture was concentrated under vacuum yielding 0.040 g of N5-(4-fluorobenzyl)-N2,3-dihydroxy-4-(methoxymethyl)-N5-methylpyridine-2,5-dicarboxamide (60% yield) as a white solid; MS-ESI m/z 364 [MH]+.