Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Si:13]([O:20][CH2:21][C:22]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:24][NH:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C.O>C1COCC1>[Si:13]([O:20][CH2:21][C:22]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:24][N:23]1[C:7]([Cl:10])=[O:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of 3.7 g (12.5 mmol) of triphosgene in THF at 0° C. was added dropwise a mixture of 2.5 g (6.2 mmol) of amine 1-8 and 1.74 mL (12.5 mmol) of triethylamine in THF. The reaction was allowed to warm to room temperature overnight with stirring. The mixture was then dumped into water, placed in a separatory funnel, and extracted twice with EtOAc. The combined organic extracts were combined, washed with water, dried over Na2SO4 and concentrated to obtain 6-1 as a brown solid. Data for 6-1: HRMS (ES) calc'd M+H for C24H28ClF2NO2Si: 464.1619. Found: 464.1625.
Reaction SMILES: [C:1]([C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([Mg]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:2]1([C:1]([OH:8])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCOC(=O)C(=O)c1ccccc1
Product: CCOC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
According to JP-A-11-193271, ethyl benzoylformate and cyclohexylmagnesium bromide are condensed to give ethyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, which is hydrolyzed to give 2-cyclohexyl-2-hydroxy-2-phenylacetic acid. In this condensation reaction, diethyl ether having a boiling point of 35° C. is used in an amount of about 12-fold volume relative to ethyl benzoylformate, manipulation of dangerous reaction using the boiling point of diethyl ether is required and the yield is as low as 53.3%. In an attempt to improve this method into an industrially safe one, the present inventors used tetrahydrofuran instead of diethyl ether as a solvent and reproduced the reaction. As a result, there occurred reduction due to Grignard reagent to produce ethyl mandelate as a by-product, as well as addition of the Grignard reagent to ester bond. The proportion of the starting material that became a by-product was 42% and the yield of the objective product was as low as 58%. After hydrolysis of the obtained crude ethyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, it was subjected to recrystallization and the like to increase the purity but the yield from ethyl benzoylformate of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid did not exceed 43%.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH:29]=[CH2:30])=[O:27]>ClCCCl>[CH3:24][C:11]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]2[CH:15]([CH2:16][N:8]([C:26]([O:28][CH:29]=[CH2:30])=[O:27])[CH2:9]2)[C:14](=[O:17])[CH2:13][CH2:12]1
Reactant: C=COC(=O)Cl
Reactant: CC1(c2ccccc2)CCC(=O)C2CN(Cc3ccccc3)CC21
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(=O)CCC(C)(c3ccccc3)C2C1

Procedure:
To a solution of 9 g of (3aRS,7SR,7aRS)-2-benzyl-7-methyl-7-phenyl-4-perhydroisoindolone in 100 cm3 of 1,2-dichloroethane are added, at room temperature, 2.84 cm3 of vinyl chloroformate, followed by heating for 2 hours at reflux. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is purified by chromatography on a Column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 23 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 100 cm3 fractions. Fractions 17 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 4.27 g of (3aRS,7SR,7aRS)-7-methyl-7-phenyl-2-vinyloxycarbonyl-4-perhydroisoindolone are obtained in the form of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)#[N:17].O>CN(C)C=O>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:1][C:2]2[C:3]([CH2:8][C:9]3[NH:13][CH:12]=[CH:11][N:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: Oc1cccnc1Cc1ncc[nH]1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(COc2cccnc2Cc2ncc[nH]2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 120.7 %

Procedure:
A solution of 3-hydroxy-2-(1-imidazolylmethyl)-pyridine (6.0 g) in dry N,N-dimethylformamide (100 ml) was cooled to 5° C. and stirred under nitrogen. Sodium hydride (1.8 g as a dispersion in mineral oil) was added and the mixture was stirred for 1 hour at room temperature and then cooled to 0° C. A solution of 4-cyano-benzylbromide (6.8 g) in dry N,N-dimethylformamide (25 ml) was added and the mixture stirred at room temperature for a further 3 hours and allowed to stand overnight. Water (250 ml) was added and the aqueous solution extracted with ethyl acetate (4×100 ml). The organic extracts were combined, washed with water, dried over MgSO4 and evaporated to yield a solid. Recrystallization from ethyl acetate gave 3-(4-cyanobenzyloxy)-2-(1-imidazolylmethyl)pyridine (12.0 g), m.p. 159° C.
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])=[S:20])=[C:14]([OH:30])[C:13]=1[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32].[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].N1C=CN=C1>>[F:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:14]=1[O:30][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2F)c1O
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2F)c1O[Si](C)(C)C(C)(C)C
Yield: 64.7 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 12, N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2,3-difluorophenyl)thiourea (418 mg, 1.0 mmol), tert-butyldimethylsilyl chloride (745 mg, 5.0 mmol) and imidazole (136 mg, 2.0 mmol) were reacted to form the desired product (347 mg, 65%). EI-MS m/z 536.2 (M+).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:17][O-:18].[Na+].O>CO>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:18][CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[O-]
Reactant: ClCCCCOc1cccc2ccccc12
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCCOc1cccc2ccccc12

Procedure:
A solution of 4-(1-naphthyloxy)-butyl chloride (3.0 g) and sodium methoxide (1.5 g) in methanol (25 ml) was refluxed for 8 hours, then poured into water and the solution extracted with ether. The extract was dried and evaporated and the residue chromatographed on silica gel, eluting with 2:1 hexane ether, to produce the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]([CH3:20])[CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[S:8][C:6]=2[N:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[CH3:20][N:12]([CH2:11][C:9]1[S:8][C:6]2[N:7]=[C:2]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]=2[CH:10]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: OB(O)c1cncnc1
Reactant: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-piperidin-4-yl)-amine was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 168. NMR (CDCl3): 1.59-1.81 (4H, m), 1.96-2.03 (2H, m), 2.25 (3H, s, Me), 2.28 (3H, s, Me), 2.44-2.52 (1H, m), 2.90-2.95 (2H, m), 3.80-3.88 (6H, m, CH2), 3.90-3.94 (4H, m, CH2), 7.10 (1H, s, Ar), 9.16 (1H, s, Ar) and 9.60 (2H, s, Ar). MS: (ESI+): MH+440.22
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.[Br-].[CH3:15][CH2:16][CH:17]([Zn+])[CH2:18][CH3:19].O>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:17]([CH2:18][CH3:19])[CH2:16][CH3:15])[CH:5]=1
Reactant: CCC([Zn+])CC
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C(=O)OC)cc(OC)n1
Temperature: 85 °C

Procedure:
Under argon, Pd(dppf) (3.04 g, 4 mmol) is added to a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (50 g, 0.248 mol) in THF (100 mL). A 0.5 M solution of 3-pentylzincbromide in THF (550 mL) is added via dropping funnel. Upon complete addition, the mixture is heated to 85° C. for 18 h before it is cooled to rt. Water (5 mL) is added and the mixture is concentrated. The crude product is purified by filtration over silica gel (350 g) using heptane:EA 7:3 to give 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid methyl ester (53 g) as a pale yellow oil; 1H NMR (CDCl3): δ0.79 (t, J=7.5 Hz, 6H), 1.63-1.81 (m, 4H), 2.47-2.56 (m, 1H), 3.94 (s, 3H), 3.96 (s, 3H), 7.12 (d, J=1.0 Hz, 1H), 7.23 (d, J=1.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[NH:16][N:17]=[C:18]([CH:19]3[CH2:21][CH2:20]3)[C:5]=12.Cl[CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[N:16]([CH2:23][C:24]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:17]=[C:18]([CH:19]3[CH2:21][CH2:20]3)[C:5]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(C3CC3)c12
Reactant: O=C(CCl)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(C2CC2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Yield: 46 %

Procedure:
Sodium hydride (60% in mineral oil, 18 mg, 0.44 mmol) was added to a solution of 4-chloro-3-cyclopropyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (100 mg, 0.37 mmol) and 2-chloro-1-(pyrrolidin-1-yl)ethanone (82 mg, 0.55 mmol) in dry DMF (3 mL) at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, CH2Cl2/diethyl ether 8:2) to provide Compound Iee as a solid (65 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[CH:4][CH:3]=1.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[O:30][CH3:31]>CO.O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][N:11]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])=[C:22]([O:30][CH3:31])[CH:23]=3)[C:10](=[O:14])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Reactant: O=c1nc(COc2ccc(Cl)cc2)cc[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Product: COc1cc(-n2ccc(COc3ccc(Cl)cc3)nc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 4-((4-chlorophenoxy)methyl)pyrimidin-2(1H)-one Part C (0.2 g, 0.845 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (0.304 g, 1.268 mmol), and copper (II) acetate monohydrate (0.169 g, 0.845 mmol) in MeOH (45 mL) and H2O (11 mL) was added N,N,N′N′-tetramethylethylenediamine (0.26 mL, 1.690 mmol). After stirring at RT for 45 minutes in the presence of air, the mixture was extracted with CH2Cl2 (200 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica gel/100:0 to 0:100 hexanes-ethyl acetate to 95:5 CH2Cl2/MeOH gradient). The product thus obtained was re-purified using prep HPLC (Phen Luna Axia C18 5μ 10:90 to 90:10 MeOH/H2O) to afford the desired product 4-((4-chlorophenoxy)methyl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one C-1 (16.9 mg, 0.036 mmol, 4.32% yield) as a yellow solid. 100 mg of starting material 4-((4-chlorophenoxy)methyl)pyrimidin-2(1H)-one was also recovered. LC/MS 431 (M+H)+, tR 0.81 min (method 5); 1H NMR (400 MHz, Chloroform-D) δ 7.73 (1H, d, J=6.78 Hz), 7.28-7.31 (2H, m), 6.94-7.03 (2H, m), 6.86-6.94 (3H, m), 6.66 (1H, d, J=7.03 Hz), 5.02 (2H, s), 3.87 (3H, s), 3.86 (2H, s), 1.36 (6H, s).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([O:13][CH2:14][CH:15]([N:22]2[C:26]3[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=3[N:24]=[C:23]2[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:11][CH:12]=1)C.[OH-].[Na+].Cl>O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:23]2[N:22]([CH:15]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][O:13][C:10]3[N:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:40])=[O:3])=[CH:12][CH:11]=3)[C:26]3[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=3[N:24]=2)=[CH:34][CH:35]=1
Reactant: CCOC(=O)COc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To a solution of 0.18 g (0.32 mmol) (6-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethoxy}-pyridin-3-yloxy)-acetic acid ethyl ester in 2 mL tetrahydrofuran 2 mL water and 0.13 mL (0.77 mmol) 32% aqueous sodium hydroxide solution were added. The mixture was stirred at 75° C. for 1.5 h and then poured on 20 mL 1M aqueous hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated to dryness. The residue was suspended in a mixture of acetonitrile and water, filtered and washed with acetonitrile to give the desired product as a white solid (61%). MS (Turbo Spray): m/z=542.3 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[Br:22]N1C(=O)CCC1=O>ClCCl>[Br:22][C:7]1[N:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A solution of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (1.94 g, 6.8 mmol) in dichloromethane (35 mL) was purged with nitrogen and cooled to 0° C. This light purple/grey homogenous solution was treated with a single portion of N-bromosuccinimide (1.34 g, 7.5 mmol) instantly becoming a lighter color. The reaction was warmed to room temperature for 15 minutes, transferred to a separatory funnel, diluted with 100 mL additional dichloromethane, washed twice with water (75 mL), and once with brine (75 mL). The organics were dried over MgSO4, filtered, and concentrated to give a golden oil. This material was purified by biotage MPLC (90 g column, 15% ethyl acetate/heptane) to afford 2.24 g (90%) of the title compound as a pale yellow solid; IR (diffuse reflectance) 3416, 3355, 2969, 2941, 1555, 1538, 1482, 1385, 1378, 1295, 1285, 1200, 1181, 1043, 733 cm−1; OAMS supporting ions at: ESI+ 361.9; MS (EI) m/z 361 (M+); [α]25D=−35 (c 0.53, methylene chloride); Anal. Calcd for C17H20BrN3O: C, 56.36; H, 5.56; N, 11.60. Found: C, 56.46; H, 5.59; N, 11.50.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[OH:28].O[CH2:30][C:31]1[C:35]([CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[C:46]4[C:51](=[CH:52][CH:53]=3)[N:50]=[C:49]([C:54]([O:56]C)=[O:55])[CH:48]=[CH:47]4)=[CH:40][CH:39]=2)=[C:34]([CH:58]([CH3:60])[CH3:59])[O:33][N:32]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+]>O1CCCC1.CO>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[O:28][CH2:30][C:31]1[C:35]([CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[C:46]4[C:51](=[CH:52][CH:53]=3)[N:50]=[C:49]([C:54]([OH:56])=[O:55])[CH:48]=[CH:47]4)=[CH:40][CH:39]=2)=[C:34]([CH:58]([CH3:60])[CH3:59])[O:33][N:32]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CO)noc4C(C)C)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(COc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 16.4 %

Procedure:
To a solution of triphenylphosphine (34 mg, 0.13 mmol), 2,6-dichlorophenol (21 mg, 0.13 mmol) and methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (56 mg, 0.13 mmol) was added diisopropyl azodicarboxylate (0.023 mL, 0.13 mmol). The solution was heated in a microwave reactor at 100° C. for 10 minutes. This heating was repeated again for 10 minutes. The mixture was adsorbed onto silica gel and purified by chromatography (silica gel, 0-60% ethyl acetate in hexanes gradient elution) to afford a solid that was dissolved in 2:1 tetrahydrofuran/methanol (1.5 mL). Then 1 N sodium hydroxide (0.13 mL, 0.13 mmol) was added. The solution was heated in a microwave reactor at 120° C. for 500 seconds. The mixture was concentrated and the residue was taken up with methanol. Then 10% aqueous citric acid was added and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with additional citric acid until the pH was approximately 2-3 and was extracted one more time with ethyl acetate. The combined organic layers were concentrated and the residue was taken up with ether which was removed under vacuum. The resulting solid was dissolved in ethyl acetate and the solution was washed with water and brine and then concentrated to afford 6-[4-({[3-{[(2,6-dichlorophenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (12 mg, 24%). 1H-NMR (400 MHz, CDCl3) δ 8.36 (d, J=9 Hz, 1H), 8.24-8.19 (m, 2H), 8.02 (d, J=10 Hz, 2H), 7.66 (d, J=9 Hz, 2H), 7.24 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 6.99-6.97 (m, 1H) 5.15 (s, 4H), 3.27 (3.27 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). HRMS (ESI) C30H24Cl2N2O5 calculated: 563.1135 (M+H)+, found: 563.1130 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2.Cl[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:24][C:23]([F:26])([F:25])[C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:13][CH2:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:11]3)[CH:22]=1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1cc(NCc2ccc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 130 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
{[2-(Trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 34, 100 mg, 0.467 mmol), 4-chloro-6-(trifluoromethyl)pyrimidine (Intermediate 26, 128 mg, 0.700 mmol) and potassium carbonate (142 mg, 1.027 mmol) were dissolved in DMSO (1 mL). The reaction mixture was stirred in the microwave for 1 hour at 130° C. The LC/MS showed product. The reaction mixture was poured into water and the product was extracted with ethyl acetate. Traces of water were removed with a phase separator. The solvent was removed under reduced pressure. Purification was done by MDAP. The most pure fractions were combined and diluted with DCM and washed with aqueous sodium bicarbonate. Traces of water were removed with a phase separator. The solvent was removed under reduced pressure to give the title compound (20 mg);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)(=[O:10])=[O:9].[C:32](OC(=O)C)(=[O:34])[CH3:33]>C1(C)C=CC=CC=1>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)(=[O:9])=[O:10])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)c3cccc(F)c3)c(N)c2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1S(=O)(=O)c1cccc(F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of tert-butyl 4-[3-amino-4-[(3-fluorophenyl)sulfonyl]phenyl]-1,4-diazepane-1-carboxylate (0.29 g, 0.66 mmol) and anhydrous acetic anhydride (1.0 mL) is stirred at 60° C. for 1 h under a nitrogen atmosphere. After cooling to rt, 5 mL of toluene is added and the mixture concentrated. The crude product is triturated with more toluene then with EtOAc and Et2O to give 0.31 g (97%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C>C(O)C>[CH3:17][N:13]1[C:14]2=[CH:15][N:22]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: CCOC(=O)CCCCN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (1.38 g, 4.09 mmol), ethyl 5-aminovalerate hydrochloride (1.109 g, 6.14 mmol) and triethylamine (1.711 mL, 12.28 mmol) were combined in ethanol (20 mL) and the mixture heated at reflux for 40 mins. The reaction mixture was cooled to room temperature and evaporated under vacuum. The residue was partitioned between water and DCM and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated onto silica. The silica was deposited onto a 25 g silica cartridge and the system eluted with 20% EtOAc/hexane, 40% EtOAc/hexane, 60% EtOAc/hexane and 80% EtOAc/hexane. The product fractions were combined and concentrated under reduced pressure to afford the title compound;