Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH2:33][CH3:34])[C:26](=[O:32])[N:27]([CH2:30][CH3:31])[C:28]=2[CH3:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH2:33][CH3:34])[C:26](=[O:32])[N:27]([CH2:30][CH3:31])[C:28]=2[CH3:29])=[CH:21][CH:22]=1)=[O:7]
Reactant: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c(=O)n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n(CC)c1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester (0.77 mmol, 0.41 g) in ethanol (2 mL) was added aqueous 1.0 N sodium hydroxide (1.5 mL) at room temperature. The mixture was heated to 50° C. and the resulting clear solution was stirred for 2 h. Then, the ethanol was removed under reduced pressure and the residue was diluted with water (25 mL) and NaOH (2 mL, 1.0N) to dissolve the sodium salt. The aqueous solution was washed with diethyl ether (30 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×25 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 320 mg (80% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C25H25Cl2N3O5 (M+Na) 541.3921, found 541.3925.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:26][C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH2:32][C:33](=[O:42])[N:34]2[CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:29][CH:28]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][C:33](=[O:42])[N:34]3[CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:29][CH:28]=2)=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)CCc2ccc(CCl)cc21
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCCOC)C(=O)CC3)cc1

Procedure:
Analogously to Method D, 3.26 g of tert-butyl 4-(4-allyloxyphenyl)-3-hydroxypiperidine-1-carboxylate and 2.62 g of 7-chloromethyl-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.16 (1:1 EtOAc-heptane); Rt=5.50.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[OH-].[K+:12]>O>[NH2:1][C@H:2]([C:8]([O-:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[K+:12]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NCCCC[C@H](N)C(=O)[O-]
Temperature: 70 °C

Procedure:
To a 500 ml 2-neck round bottom flask, equipped with a reflux condenser and a pressure equalizing addition funnel was charged 10.00 parts (0.068 eqv.) of lysine. 101 ml of KOH (0.065 eqv.) was added to the addition funnel. The basic solution was added to the lysine, with magnetic stirring, over about 4 minutes. The reaction mixture was then stirred at about 70° C. for an additional hour, to insure complete reaction. The water was stripped off the reaction product at about 10 mm Hg and about 70° C. The yellowish wax was broken up and dried overnight at about 80° C and at about 2 mm Hg. The yellowish wax was then stored in a dry, airtight container.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Reactant: Brc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=S(=O)(CCc1ccc(F)cc1)N1CCC(CNc2ncccn2)CC1

Procedure:
A mixture of 0.3 g of C-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-yl}-methylamine, 0.3 g of 2-bromopyrimidine, 25 mL of 2-propanol and 0.3 mL of N,N-diisopropylethylamine was heated to reflux overnight. Purification of the residue obtained after concentration under reduced pressure by preparative chromatography, eluting with ethyl acetate gave a white solid.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]2[CH:8]=[CH:7]1)(C)(C)C.Cl>CO>[CH3:15][C:13]1[CH:14]=[C:9]2[CH:8]=[CH:7][NH:6][C:10]2=[N:11][CH:12]=1
Reactant: Cc1cnc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: Cc1cnc2[nH]ccc2c1
Yield: 80.4 %

Procedure:
To a stirred solution of the crude azaindole 8 (0.64 mmol) in MeOH (6 mL) was added a 10% solution of HCl in methanol (3 mL). After 20 min the mixture was concentrated and partitioned between AcOEt and saturated aqueous NaHCO3 solution. The aqueous layer was extracted with AcOEt (2×) and the combined organic solutions were dried (MgSO4), filtered and concentrated. The residue was purified by PTLC using 5% MeOH in CH2Cl2 to afford the desired methyl derivative 9 (68 mg, 81% over 3 steps). 1H NMR (400 MHz; CDCl3) δ 2.45 (s, 3H), 6.42 (d, J=3.4 Hz, 1H), 7.34 (d, J=3.4 Hz, 1H), 7.76 (d, J=1.7 Hz, 1H), 8.19 (d, J=1.7 Hz, 1H), 10.92 (br s, NH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC([C@@H]2C(=O)[N:39]([C@@H:42]([C@H:55]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH3:56])[C:43]([NH:45][C:46]3[S:47][CH:48]=[C:49]([C:51](=[O:54])[CH2:52][CH3:53])[N:50]=3)=[O:44])C(=O)N2)=CC=1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:17][CH:18]=1)[C:10](=[O:12])[NH:39][C@H:42]([C:43](=[O:44])[NH:45][C:46]1[S:47][CH:48]=[C:49]([C:51](=[O:54])[CH2:52][CH3:53])[N:50]=1)[C@H:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH3:56])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OC)cc3)C2=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCN2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OCCN3CCOCC3)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
(R)-tert-butoxycarbonylamino-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetic acid (≈2.93 mmol) was dissolved in tetrahydrofuran (60 mL) and (2S,3S)-2-amino-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (500 mg, 1.58 mmol) (prepared as described in example 4) was added followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (600 mg, 3.12 mmol) at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After stirring for 5.5 hours the reaction mixture was partitioned between ethyl acetate and brine, the organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting residue purified by chromatography over silica gel eluted first with ethyl acetate and then gradient eluted with dichloromethane containing from 0 to 10% methanol. {(R)-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-[(1S,2S)-2-phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl]-methyl}-carbamic acid-tert-butyl ester was obtained as a white solid (146 mg, 14%).
Reaction SMILES: [C:1]([N:9]([C:16]1[CH:17]=[C:18]([CH2:22][C:23]([O:25]C)=[O:24])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+].CO>[C:1]([N:9]([C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cccc(N(C(=O)c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(N(C(=O)c2ccccc2)c2ccccc2)c1
Yield: 87.4 %

Procedure:
The ester (600 mgs, 1.9 mmol) in 4N sodium hydroxide (20 ml) and methanol (20 ml) was stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in water (10 ml) and acidified with 5N hydrochloric acid. The acidic solution was extracted with dichloromethane (3×50 ml), and the combined organics dried and evaporated to afford 3-(N-benzoylanilino)phenylacetic acid as an oil (550 mgs); δH (CDCl3) 3.59 (2H, s, CH2CO2H), 6.83-7.29 (10H, m, ArH), 7.42-7.48 (3H, m, ArH), 8.09 (2H, d, J 7.2 Hz, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[F:24][C:20]1[C:21]([F:23])=[CH:22][C:2]2[N:1]=[C:14]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:19]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2cc(F)c(F)cc2N)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3cc(F)c(F)cc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-4,5-difluoroanilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 8,9-difluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([CH:26]([CH3:28])[CH3:27])[C:19]2=[O:29].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.C(O)(=O)C>ClCCl>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[N:20]([CH:26]([CH3:27])[CH3:28])[C:19]3=[O:29])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)N1C(=O)c2ccc(N)cc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1C(=O)c2ccc(NCc3ccc(Cl)cc3)cc2C1=O
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Sodium triacetoxyborohydride (1.03 g, 4.90 mmol) was added to a stirred solution of 5-amino-2-isopropyl-isoindole-1,3-dione (0.50 g, 2.69 mmol), 4-chlorobenzaldehyde (0.37 g, 2.69 mmol), and acetic acid (160 μl, 2.69 mmol) in anhydrous dichloromethane (10 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (5% methanol in dichloromethane) to afford the title compound as a light brown solid (160 mg, 20%). HPLC retention time 4.86 min. Mass spectrum (ES+) m/z 329 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=2[N:18]=1.[H-].[Na+].[CH3:21]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]([CH3:16])[CH3:17])[C:6]=2[N:18]=1
Reactant: CI
Reactant: CC(C)N1CC(F)(F)C(=O)Nc2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
2-chloro-7,7-difluoro-9-isopropyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (0.800 g, 2.89 mmol) was dissolved in DMA (7 mL) and cooled to 0° C. under nitrogen. NaH (140 mg, 3.50 mmol) was added, the mixture was stirred for 20 min and MeI (0.23 mL, 3.61 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h and quenched with water (25 mL). The pH was adjusted to 1 (aq. HCl) and the mixture was extracted with ethyl acetate (4×20 mL). The comb organic extracts were concentrated in vacuo, dissolved in dichloromethane/trifluoroacetic acid (5:1, 6 ml) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (80 g SiO2, hexanes:ethyl acetate 1:1) to afford the title compound as a yellow solid (0.753 g, 90%).
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[NH2:13][C:14]([NH:16][C:17]1[NH:18][C:19]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=2)=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23])=[O:15].O>CS(C)=O>[NH2:13][C:14]([NH:16][C:17]1[NH:18][C:19]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=2)=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23])=[O:15]
Reactant: NC(=O)Nc1[nH]c(-c2ccc(CO)cc2)cc1C(N)=O
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Nc1[nH]c(-c2ccc(C=O)cc2)cc1C(N)=O
Yield: 67 %

Procedure:
2-Iodoxybenzoic acid (150 mg, 0.53 mmol) was added to a solution of 2-aminocarbonylamino-5-(4-hydroxymethylphenyl)pyrrole-3-carboxamide (Compound No. 13-1, 130 mg, 0.47 mmol) in dimethyl sulfoxide (5 mL) and the mixture was stirred at room temperature for 1 hour. Water (15 mL) was added to the reaction solution, the precipitated solid was filtered off. The obtained solid was washed with 0.25N aqueous sodium hydroxide (2 mL) and water (2 mL), dried under reduced pressure to give the target compound (86 mg) as a yellow solid (Yield 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]1=[O:24].Cl[C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:32][C:31]1[C:26]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([N:16]4[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]4=[O:24])=[C:2]([F:1])[CH:7]=3)=[O:9])[CH2:11][CH2:12]2)=[N:27][CH:28]=[C:29]([Cl:33])[CH:30]=1
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1F
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)cc1F
Temperature: 100 °C
Yield: 48.8 %

Procedure:
(R)-3-[2-fluoro-4-(piperazine-1-carbonyl)phenyl]-4-methoxymethyloxazolidin-2-one (343 mg) described in Preparation Example 94 was dissolve in N,N-dimethylformamide (2 mL), 2,3,5-trichloropyridine (275 mg) and potassium carbonate (562 mg) were added and the mixture was stirred at 100° C. To the reaction mixture was added ethyl acetate under ice-cooling and insoluble materials were filtered off. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (chloroform:methanol) to give the title compound (240 mg).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[CH:13]=2)[CH2:8][CH2:7]1)[CH3:4].Cl[CH:21]([F:23])[F:22].C(=O)=O>C1COCC1>[CH2:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:21]([F:23])[F:22])=[C:14]([F:19])[CH:13]=2)[CH2:10][CH2:11]1)[CH3:4]
Reactant: FC(F)Cl
Reactant: CCO[C@H]1CC[C@H](c2ccc(O)c(F)c2)CC1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCO[C@H]1CC[C@H](c2ccc(OC(F)F)c(F)c2)CC1
Reaction time: 1 h

Procedure:
11 g of NaOH (32%) are added to a solution of 8.2 of the resultant p-(trans-4-ethoxycyclohexyl)-o-flurophenol in 80 ml of THF and 13.8 g of chlorodifluoromethane are introduced (dry ice reflux condenser). After subsequently stirring for one hour, the solution is decanted off from the precipitate and concentrated to give a residue. Bulb tube distillation gives p-(trans-4-ethoxycyclohexyl)-o-fluorodifluoromethoxybenzene, b.p.1 ~220° C., Tg -62°.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:3])=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:41][O:40][C:38]1[CH:39]=[C:34]([NH:33][C:31](=[O:32])[CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([NH:23][C:1]([C:4]3[C:5]([C:15]4[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:22])=[N:6][O:7][C:8]=3[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:3])[CH:25]=2)[CH:35]=[C:36]([O:44][CH3:45])[C:37]=1[O:42][CH3:43]
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)c3c(-c4c(F)cccc4Cl)noc3-c3ccccc3)c2)cc(OC)c1OC
Reaction time: 14 h
Yield: 64.5 %

Procedure:
To a solution of 4-carboxy-5-phenyl-3-(2-chloro-6-fluorophenyl)isoxazole (0.135 g, 0.425 mmol) and 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (0.129 g, 0.408 mmol) in dichloromethane (5 ml) was added EDCI (0.082 g, 0.51 mmol) and DMAP (0.062 g, 0.51 mmol) and stirred for 14 h. The mixture was applied to a silica gel chromatography column. Elution with hexanes and ethyl acetate (gradient) gave the title compound (0.162 g, 64%).
Reaction SMILES: N#N.[Br:3][C:4]1[C:9]([F:10])=[CH:8][C:7](I)=[CH:6][C:5]=1[F:12].[Li]CCCC.[C:18](=O)=[O:19].S(C)C>CCOCC.CC(=O)OCC.Cl.C1COCC1.O>[Br:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH2:18][OH:19])=[CH:6][C:5]=1[F:12]
Reactant: O=C=O
Reactant: Fc1cc(I)cc(F)c1Br
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CSC
Solvent: CCOCC
Product: OCc1cc(F)c(Br)c(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-3,5-difluoroiodobenzene (790 mg, 2.48 mmol) in dry Et2O (12 mL) was added to a n-BuLi (0.98 mL of a 2.5M solution in hexanes, 2.45 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 2 h before solid CO2 was added. The reaction mixture was stirred at −78° C. for 10 min and then allowed to warm up to rt. The mixture was then diluted with EA and aq. 1N HCl was added. The layers separated and the org. layer dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the crude carboxylic acid as a pale yellow solid. The crude material (270 mg, 1.14 mmol) was dissolved in dry THF (6 mL) and treated with BH3.Me2S complex (1.0 M in THF, 2.3 mL, 2.30 mmol) at 0° C. The reaction mixture was then warmed to 50° C. and stirred at this temperature until completion of the reaction. The mixture was cooled to 0° C. and water was added followed by EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 9:1 to 2:1) to give the title compound as a white solid. TLC:rf (1:1 EA-hept)=0.53.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][P:8](=[O:17])([O:13][CH:14]([CH3:16])[CH3:15])[O:9][CH:10]([CH3:12])[CH3:11])([O-])=O.Cl[C:22]1[N:27]=[C:26]([NH:28][CH2:29][C:30]2[C:31]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]([C:42]([F:45])([F:44])[F:43])=[CH:24][N:23]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>CO.[Pd]>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[CH3:41][N:36]([S:37]([CH3:40])(=[O:39])=[O:38])[C:31]1[C:30]([CH2:29][NH:28][C:26]2[C:25]([C:42]([F:45])([F:43])[F:44])=[CH:24][N:23]=[C:22]([NH:1][C:4]3[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=3)[CH2:7][P:8](=[O:17])([O:13][CH:14]([CH3:16])[CH3:15])[O:9][CH:10]([CH3:12])[CH3:11])[N:27]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CC(C)OP(=O)(Cc1cccc([N+](=O)[O-])c1)OC(C)C
Reactant: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)OP(=O)(Cc1cccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)c1)OC(C)C
Yield: 34 %

Procedure:
A mixture of triisopropyl phosphite (500 mg, 2.31 mmol) and 1-bromomethyl-3-nitrobenzene (506 mg, 2.43 mmol) was heated at 100° C. under nitrogen for 3 h. The crude dipropan-2-yl (3-nitrobenzyl)phosphonate thus formed was dissolved in MeOH (5 mL) and hydrogenated in the presence of 5% Pd/C (49 mg) for 2 h. The mixture was filtered and concentrated in vacuo and the dipropan-2-yl (3-aminobenzyl)phosphonate residue heated in a microwave reactor at 105° C. under nitrogen for 40 minutes with N-[3-({[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide XLIa (20 mg, 0.051 mmol), TFA (12 uL, 0.15 mmol) and 0.5 mL TFE. The mixture was evaporated to dryness and purified by preparative HPLC to afford 11 mg of dipropan-2-yl [3-({4-[({2-[methyl (methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate trifluoroacetate (Example 35, yield: 34%). 1H NMR (400 MHz, CD3OD) δ=1.19 (d, J=6.1 Hz, 6 H), 1.28 (d, J=6.1 Hz, 6 H), 3.06-3.12 (m, 4 H), 3.12-3.19 (m, 4 H), 4.51-4.63 (m, 2 H), 4.96 (s, 2 H), 7.14 (d, J=7.3 Hz, 1 H), 7.21-7.28 (m, 1 H), 7.29-7.33 (m, 1 H), 7.35-7.43 (m, 2 H), 7.76 (d, J=7.6 Hz, 1 H), 8.21 (s, 1 H), 8.45 (dd, J=4.8, 1.8 Hz, 1 H). MS (ES+): m/z 631.27 (100) [MH+]; HPLC: tR=1.03 min (UPLC, purity).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:7]=[N:8][C:9]([N+:12]([O-])=O)=[CH:10][CH:11]=1.[C:16]1([C:22]2[O:23][C:24]([C:30]([F:33])([F:32])[F:31])=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:27]([C:25]2[N:26]=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:23][C:24]=2[C:30]([F:32])([F:33])[F:31])=[O:28])=[N:8][CH:7]=1
Reactant: COCCN(C)c1ccc([N+](=O)[O-])nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)nc1

Procedure:
With a procedure similar to example 66 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {5-[(2-methoxy-ethyl)-methyl-amino]-pyridin-2-yl}amide was prepared from (2-methoxyethyl)-methyl-(6-nitropyridin-3-yl)-amine and 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid. The product was isolated as a yellow solid (200 mg, 37% yield). HRMS m/z calcd for C20H19F3N4O3 [M+H]+: 421.1482; Found: 421.1481.