Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:41])[NH:32][C:33]5[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=5)=[CH:27][C:26]=4[NH:42][C:43]4[C:44]5[CH:52]=[CH:51][C:50]([CH:53]([CH3:55])[CH3:54])=[N:49][C:45]=5[N:46]=[CH:47][N:48]=4)=[CH:20][CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:32][C:33]3[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)=[O:41])=[CH:27][C:26]=2[NH:42][C:43]2[C:44]3[CH:52]=[CH:51][C:50]([CH:53]([CH3:55])[CH3:54])=[N:49][C:45]=3[N:46]=[CH:47][N:48]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2ccc(Sc3ccc(N)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cn1
Temperature: 70 °C
Yield: 76.6 %

Procedure:
A solution of the product of Example 201C (121.8 mg, 0.1603 mmol) in 1,4-dioxane (3 mL) was treated with a solution of lithium hydroxide monohydrate (13.5 mg, 0.3206 mmol) in water (1.5 mL) at ambient temperature, then heated at 70° C. for 30 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (75 mL) and water (30 mL), adjusted the aqueous pH to 6 with 1N aqueous hydrochloric acid, and separated the layers. The organic phase was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel flash chromatography with 6% methanol/methylene chloride afforded the title compound as a light yellow solid (66 mg, 77%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.05-3.39 (m, 1 H) 3.83 (s, 3 H) 5.59 (s, 2 H) 6.64 (d, J=8.46 Hz, 2 H) 6.82 (d, J=8.82 Hz, 1 H) 6.88 (dd, J=7.35, 1.84 Hz, 1 H) 7.14 (d, J=8.46 Hz, 2 H) 7.57-7.69 (m, 1 H) 7.73-7.85 (m, 1 H) 7.89-7.99 (m, 1 H) 8.01 (dd, J=9.01, 2.76 Hz, 1 H) 8.48 (d, J=2.57 Hz, 1 H) 8.52-8.66 (m, 1 H) 8.83-8.98 (m, 1 H) 10.16 (s, 1 H) 10.20 (s, 1 H); MS (ESI+) m/z 538 (M+H)+, 560 (M+Na)+, (ESI−) m/z 536 (M−H)−.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1)=[O:4].BrBr.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>C(Cl)Cl.C(OCC)C>[Cl:11][C:9]1[CH:10]=[C:5]([C:3]2([OH:4])[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[NH:15][CH:2]2[CH3:1])[CH:6]=[C:7]([Cl:12])[CH:8]=1
Reactant: CC(C)(N)CO
Reactant: CCC(=O)c1cc(Cl)cc(Cl)c1
Agent: BrBr
Solvent: CCOCC
Solvent: ClCCl
Product: CC1NC(C)(C)COC1(O)c1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of 3,5-dichloropropiophenone (8m, 3.81 g, 0.0188 mol) in CH2Cl2 (28 mL) was added bromine (0.986 mL, 19.1 mmol) dropwise. The bromine was immediately consumed upon addition of each drop until the end of addition when it had a consistent brownish color, indicative of excess bromine. The reaction was immediately quenched with saturated aqueous NaHCO3, extracted three times with CH2Cl2. The organic layer was separated, combined and concentrated under reduced pressure, without drying to afford a yellow oil. The oil was dissolved in anhydrous diethyl ether (50 mL) and 2-amino-2-methyl-1-propanol (6.7 g, 0.075 mol) was added. The reaction mixture was stirred overnight and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted three times with CH2Cl2, and the organic layers concentrated to afford another yellow oil. Purification by column chromatography on silica gel afforded 2.51 g (46%) of the title compound. The hemi-fumarate salt was prepared by dissolving the free base in methanol and adding 1.0 g of fumaric acid to form the title compound: mp 188-190° C.; 1H NMR (DMSO-d6) δ 7.58-7.57 (m, 1H), 7.47 (m, 2H), 6.67 (s, 0.5H), 4.09 (d, 1H, J=11.9 Hz), 3.53 (d, 1H, J=12.0 Hz), 3.41-3.37 (m, 1H), 1.53 (s, 3H), 1.28 (s, 3H), 1.02 (d, 3H, 6.6 Hz); 13C NMR (DMSO-d6) δ 134.9, 133.6, 127.7, 125.2, 94.7, 67.2, 52.5, 50.1, 25.0, 21.6, 14.6; Anal. (C15H19Cl2NO4.0.25H2O) calcd: C, 51.08; H, 5.57; N, 3.97. found: C, 51.13; H, 5.64; N, 3.90.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=O)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].O1C2C=CC=CC=2CC(=O)N1.C(Cl)(=O)C(Cl)=O>CN(C=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:28]([C:27]3[CH:31]=[CH:32][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:25][CH:26]=3)[O:10][C:9](=[O:11])[C:8]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C1Cc2ccccc2ON1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a mixture of 5-nitroanthranilic acid (24.59 g, 135 mmol) and pyridine (14.19 mL, 175.5 mmol, 1.3 eq) in DMF (140 mL) at 0° C., under N2, was added 4-t-butylbenzoyl chloride (31.64 mL, 162 mmol, 1.2 eq) over 15 min. After warming to room temperature, the reaction mixture was heated to 80 ° C. for 4 h. The reaction mixture was cooled and poured into 700 mL ice-water and stirred to break up the solid material. Filtration, with water followed with 1:2 Et2O:hexane washes, and vacuum drying (150° C./13 Pa/2 h) afforded a light brown solid as a mixture of acid and benzoxazinone (37.1 g, 80%). The solid was suspended in DMF (0.4 mL, 5.4 mmol, 0.05 eq) and methylene chloride (200 mL), under N2, and oxalyl chloride (10.4 mL, 119.2 mmol, 1.1 eq) was added dropwise. Vigorous gas evolution was observed. The solid went into solution over 2 h. The mixture was concentrated to a volume of about 125 mL (cold) in vacuo and filtered to give a light tan solid (about 10 g). A second crop was about 85% pure (about 10 g). The mother liquor was evaporated to dryness an d vacuum dried (80 ° C./13 Pa/3 h) to afford a light brown solid product, 95% pure (about 12 g). Total yield 93.6%.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[CH:40]1([NH2:46])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([NH:46][CH2:1][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[C@@H:21]3[CH2:30][CH2:29][C:28]4[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=4[CH2:22]3)=[CH:38][CH:39]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NC1CCCCC1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCNC3CCCCC3)cc2)c1
Yield: 15.3 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (31 mg) and cyclohexylamine (9.3 mg) according to an analogous synthetic method to Example 806, the title compound (4.6 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C@H:10]1[C@@H:15]([OH:16])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1.ClC1N=C(OC2CCN(C(OC(C)(C)C)=O)CC2)C=NC=1>>[Cl:8][C:4]1[N:3]=[C:2]([O:16][C@H:15]2[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:11][C@H:10]2[F:9])[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1
Reactant: Clc1cncc(Cl)n1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2cncc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cncc(Cl)n2)[C@H](F)C1

Procedure:
tert-butyl cis-4-[(6-chloropyrazin-2-yl)oxy]-3-fluoropiperidine-1-carboxylate was prepared from 2,6-dichloropyrazine and tert-butyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate using the conditions described for the preparation of tert-butyl 4-[(6-chloropyrazin-2-yl)oxy]piperidine-1-carboxylate (Compound 1, Step 3). LRMS (ESI) calculated for C14H19ClFN3O3[M+Na]+, 354.1; found 354.1.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH2:36])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH:36][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=2[NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:13])=[O:14])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: CC(CNC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.97 min. MS (ESI+): mass calcd. for C24H19Cl2IN4O3S, 639.96; m/z found, 641/643 [M+H]+; m/z found, 663/665 [M+Na]+. 1H NMR (400 MHz, CDCl3): 11.07 (s, 1H), 9.03 (d, J=1.8, 1H), 8.95 (d, J=1.8, 1H), 8.56 (dd, J=7.4, 1.4, 1H), 8.33 (dd, J=8.5, 1.4, 1H), 8.05 (d, J=1.6, 1H), 7.91-7.87 (m, 1H), 7.39 (d, J=8.2, 1H), 7.28-7.24 (m, 2H), 7.02 (dd, J=8.3, 2.1, 1H), 6.75 (d, J=8.2, 1H), 5.81 (s, 1H), 3.68-3.61 (m, 1H), 3.31-3.24 (m, 1H), 3.00-2.95 (m, 1H), 1.29 (d, J=7.0, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:23])[CH:15]([NH2:22])[CH2:16][S:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:23])[CH:15]([NH:22][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][S:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH3:12]
Reactant: CCOC(=O)C(N)CSC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: CCOC(=O)C(CSC(C)(C)C)NC(=O)c1ccccc1
Yield: 60 %

Procedure:
With General procedure D, starting from 21 (5.94 g, 42.26 mmol) and 12 (8.54 g, 35.36 mmol), 6.56 g (60%) of the title compound was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, 2H), 7.52 (m, 3H), 6.97 (br d, 1H), 5.06 (m, 1H), 4.28 (q, 2H), 3.16 (m, 2H), 1.32 (m, 12H). MS m/z 310 (M+1). HPLC: 98.35% (ACQ_PA95_C_BLS; Column: BEH_C18—2−1×50 mm—1-7 μm).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:7]1[C:2]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CCCCN
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 76 %

Procedure:
A procedure similar to that of the method described in step C.1 is carried out, starting from 1.2 g (5.9 mmol) of 2-chloro-3,5-dinitropyridine, 1.03 g (7.07 mmol) of ethyl 5-aminovalerate and 0.9 g (8.84 mmol) of triethylamine in 20 ml of dioxane. This gives 1.4 g of expected product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]#[N:19])=[CH:6][C:5]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:4]([F:27])[CH:3]=1.O1CCCC1>C(O)(=O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:27])=[C:5]([NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])[CH:6]=2)=[C:10]([C:18]#[N:19])[CH:11]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Oc1cc(NC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cc(N)ccc1Oc1cc(NC(=O)C(F)(F)F)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of N-[4-chloro-5-(2-cyano-4-nitrophenoxy)-2-fluorophenyl]-2,2,2-trifluoroacetamide (16.0 g, 39.6 mmol) in acetic acid (850 ml)/tetrahydrofuran (500 mL) was added reduced iron (11.1 g, 198 mmol), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off through a pad of celite, and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (900 mL)/tetrahydrofuran (100 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (500 mL) and saturated brine (500 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=10/90→50/50), and the obtained solution was concentrated under reduced pressure to give the title compound (12.2 g, 82%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][CH2:17]2)=[O:15])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29].C(=O)(O)[O-].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[C:4]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])[S:5][C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)s2)CN1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Cl)c3)c(-c3cccc(Cl)c3)s2)CN1
Temperature: 150 °C

Procedure:
Under argon, 70.0 mg of the compound from Example 24A having a purity of 76% (0.14 mmol) and 47.5 mg (0.27 mmol) of 3-chloro-4-fluorophenylboronic acid are provided in 2.6 ml of 1,2-dimethoxyethane, and 1.0 ml (0.91 mmol) of an aqueous sodium bicarbonate solution (10%) and 6.3 mg (0.005 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated in a closed glass vessel at 150° C. under microwave irradiation for 5 minutes. The reaction mixture is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient with addition of 0.1% formic acid) and additional preparative thin-layer chromatography (silica gel; mobile phase: ethyl acetate). 8.0 mg (13% of theory) of the title compound are obtained.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([Br:24])=[CH:12][C:11]=1[C:25](=[O:27])[CH3:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl>C(O)C>[CH2:32]([O:31][C:29](=[O:30])[C:28](=[O:34])[CH2:26][C:25]([C:11]1[CH:12]=[C:13]([Br:24])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:10]=1[O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:27])[CH3:33]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
9.75 g sodium (0.424 mol, 3 eq) were dissolved in 500 ml absolute ethanol (1.5 hours). 58 g of 1-(2,4-Bis-benzyloxy-5-bromo-phenyl)-ethanone (0.141 mol, 1 eq) and 30.98 g diethyl oxalate (0.212 mol, 1.5 eq) were added and the mixture was refluxed for 2 hours. After cooling down, the mixture was poured onto 220 ml of 2N aqueous HCl and the product was extracted into 700 ml dichloromethane. The solvent was removed under reduced pressure and the yellow residue was triturated with 150 ml diethyl ether.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18].Cl>O.O1CCOCC1>[CH3:20][O:19][C:17]([N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18]
Reactant: COC(=O)Cl
Reactant: CNCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N(C)CCCC(=O)O
Temperature: 25 °C
Yield: 170.4 %

Procedure:
4-(Methylamino)butyric acid hydrochloride (5 g, 32.5 mmol), and potassium carbonate (18 g, 130 mmol) were suspended in water (50 ml) and dioxane (25 ml) then cooled to 0° C. Methyl chloroformate (13 ml, 168 mmol) was added over 1 minute, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 4-[(methoxycarbonyl)(methyl)amino]butyric acid as a thick clear oil (9.7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:40])=[N:37][CH:38]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:24][C:22]1[CH:23]=[C:2]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:40])=[N:37][CH:38]=2)[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:21]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(-c2ccc(Cl)cc2)cc1)c1cc(Cl)cc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)cc(C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)c2)cn1
Temperature: 25 °C

Procedure:
3-bromo-5-chloro-N-(4′-chloro-[1,1′-biphenyl]-4-yl)benzamide (51 mg, 0.12 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (66 mg, 0.16 mmol), Pd(dppf)Cl2 (9 mg, 0.01 mmol), and 2M aqueous K2CO3 (0.12 mL, 0.24 mmol) were dissolved in 1,4-dioxane (2 mL) and water (2 mL) and the resulting mixture was heated to 70° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: ClCCNC([N:7]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:14]([NH:16][CH2:17][CH2:18]Cl)=[O:15])=[N:8]1)=O.[O-]CC.[Na+].[Na].C(O)C>C1COCC1>[CH3:12][C:11]1[NH:7][N:8]=[C:9]([N:13]2[CH2:18][CH2:17][NH:16][C:14]2=[O:15])[CH:10]=1
Reactant: Cc1cc(NC(=O)NCCCl)nn1C(=O)NCCCl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(N2CCNC2=O)n[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-[3-(2-Chloro-ethyl)-ureido]-5-methyl-pyrazole-1-carboxylic acid (2-chloro-ethyl)-amide (14.5 g, 47.05 mmol) in THF (100 mL) was added sodium ethoxide solution prepared from sodium (2.2 g, 95.65 mmol) and ethanol (100 mL) and then the reaction mixture was stirred at RT for 20 h. Precipitation of white solid was observed. The reaction mixture was cooled to 0° C. and stirred for ˜2 h. The precipitated solid was collected by filtration, washed with ethanol and water, and dried under vacuum.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC.O.C(O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=2[CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3Br)CC2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1

Procedure:
A mixture of EXAMPLE 2A (13.83 g), 4-chlorophenylboronic acid (7.04 g), bis(triphenylphosphine)palladium dichloride (481 mg) and 2M sodium carbonate (22.5 mL) in 7:3:2 DME/water/ethanol (200 mL) at 90° C. was stirred for 4.5 hours and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was flash chromatographed on silica gel with 5%-40% ethyl acetate/hexanes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].Br[CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([CH2:2][OH:1])[CH:4]=1)[CH3:15]
Reactant: CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(CO)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxymethyl-4-nitro-phenol (510 mg, 3.0 mmol) in 5 mL of dry DMF was added bromoethane (540 mg, 5.0 mmol) and K2CO3 powder (500 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H2O, extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford (5-ethoxy-2-nitro-phenyl)-methanol as a pale yellow oil: 1H NMR (CDCl3, 500 MHz) δ 8.20 (d, 1H), 7.36 (s, 1H), 6.89 (m, 1H), 5.00 (s, 2H), 4.16 (q, 2H), 2.57 (br t, 1H), 1.49 (t, 3H).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>C(Cl)(Cl)Cl>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 6 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in chloroform (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in chloroform was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 6 hours. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 137.3 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1>CN(C=O)C>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([NH:7][CH3:8])=[O:6])=[CH:16][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CNC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(Oc2ccc(N)c([N+](=O)[O-])c2)c1
Temperature: 80 °C

Procedure:
To a solution of 3-hydroxy-N-methyl-benzamide (Step A, 700 mg, 4.6 mmol, 1.0 eq.) in anhydrous DMF (10 mL) was added NaH (200 mg, 5.1 mmol, 1.1 eq.). The reaction was stirred for 10 min. at RT after which 4-chloro-2-nitro-phenylamine (2.0 g, 11.6 mmol, 2.5 eq.) was added. The resulting mixture was heated to 80° C. for 4 h. The reaction was quenched with NaHCO3 (aq.), diluted with CH2Cl2 (50 mL), and washed with 1 N NaOH (25 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-100% EtOAc in hexanes) to give pure 3-(4-amino-3-nitro-phenoxy)-N-methyl-benzamide.