Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+]>C(O)C.[Cu]>[F:13][C:4]1[CH:3]=[C:2]([NH:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: CCCCCCCCBr
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCNc1ccc(C(=O)OCC)c(F)c1

Procedure:
A mixture of 33 g of ethyl 4-amino-2-fluorobenzoate, 44 ml of 1-bromooctane and 0.50 g of copper powder is heated on a steam bath for 19 hours. The mixture is chilled, diluted with ethanol, filtered and the solid washed with cold ethanol and with water to give tan crystals. The filtrate is neutralized with 10 N potassium hydroxide, chilled and filtered and the solid washed with water and with ethanol to give tan crystals. The two crops of crystals are combined and recrystallized from ethanol to yield ethyl 2-fluoro-4-(octylamino)benzoate as a white solid.
Reaction SMILES: C(OC(=O)[N:7]=[C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:22][CH2:21]2)[C:11]2[CH:39]=[CH:40][CH:41]=[CH:42][C:10]=2[N:9]1[CH2:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:28]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:23]1[CH2:22][CH2:21][N:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:11]3[CH:39]=[CH:40][CH:41]=[CH:42][C:10]=3[N:9]([CH2:43][CH2:44][CH2:45][O:46][C:47]3[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=3)[C:8]2=[NH:7])[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1
Reaction time: 1 h
Yield: 3.2 %

Procedure:
To [1-[2-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-ylidene]-carbamic acid tert-butyl ester (100 mg, 0.14 mmol) at rt was added 25% TFA in dichloromethane (5 ml). The reaction was stirred for 1 h and then concentrated under reduced pressure. The crude product was purified by preparative HPLC and then partitioned between saturated NaHCO3 and dichloromethane. The organic phase was separated, washed with H2O, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-[2-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (2.8 mg, 3%). HPLC-MS 626 [M+1]+, 324.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][NH2:45])[CH2:39][CH2:38]1>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:45][CH2:44][CH2:43][N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:3])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CN1CCN(CCN)CC1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCN4CCN(C)CC4)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-[2-(4-methyl-piperazin-1-yl)-ethyl]-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and 2-(4-methyl-piperazin-1-yl)-ethylamine in an analogous manner to Example 1396. Product isolated as a yellow foam (16 mg, 25%). LCMS (m/e) 593 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.18 (s, 1H), 8.68 (d, 1H, J=8.5 Hz), 8.10 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.48-7.41 (m, 1H), 7.36 (s, 1H), 7.30-7.21 (m, 1H), 7.15-7.07 (m, 1H), 7.03 (d, 1H, J=8.0 Hz), 7.00 (s, 1H), 6.97-6.90 (m, 1H), 3.60-3.53 (m, 4H), 3.39 (s, 3H), 2.97-2.88 (m, 4H), 2.82-2.70 (m, 6H), 2.64 (t, 2H, J=5.7 Hz), 2.63-2.37 (m, 8H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH2:10]1[CH2:14]OC[CH2:11]1>>[CH3:1][C:2]1[S:3][C:4]([CH:8]([OH:9])[CH:10]([CH3:14])[CH3:11])=[C:5]([CH3:7])[N:6]=1
Reactant: C1CCOC1
Reactant: Cc1nc(C)c(C=O)s1
Product: Cc1nc(C)c(C(O)C(C)C)s1
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dimethylthiazole-5-carbaldehyde (1.07 g, 7.58 mmol) in THF (12 mL) was cooled to 0° C. Isopropyl magnesium chloride LiCl complex (1.3 M in THF, 6 mL, 8.8 mmol) was then added dropwise. After 30 minutes, the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to afford an orange oil. Chromatography on silica gel (5% acetone-DCM increasing to 30% acetone) provided the title compound as a light amber oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]=[CH:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]4)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([C:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]4)=[O:14])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C=CCOc1ccc2[nH]c(=O)ccc2c1)N1CCN(c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N1CCN(c2ccccc2)CC1
Reaction time: 5 h

Procedure:
1.0 Gram of 6-[3-(4-phenyl-1-piperazinylcarbonyl)-2-propenyloxy]carbostyril was dissolved in 50 ml of methanol, then 0.1 g of 5% palladium-carbon was added thereto. The mixture was catalytically hydrogenated at a room temperature under an atmospheric pressure for 5 hours. After the reaction was completed, the catalyst was removed by filtration and the filtrate was concentrated by distillation under a reduced pressure to dryness. The residue thus obtained was recrystallized from chloroform-petroleum ether to obtain 0.75 g of 6-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]carbostyril as in the form of colorless needle-like crystals. Melting point 202.5°-203.5° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][Cl:5].[Cl:8][CH2:9]C(O)CO>CC1C=CC(S(O)(=O)=O)=CC=1>[Cl:5][CH2:4][CH:3]1[O:6][CH:7]([CH2:9][Cl:8])[CH2:1][O:2]1
Reactant: COC(CCl)OC
Reactant: OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: ClCC1COC(CCl)O1
Yield: 93.6 %

Procedure:
124 g (1 mol) of chloroacetaldehyde dimethyl acetal and 110 g (1 mol) of 3-chloro-1,2-propanediol are heated together with 0.3 g p-TSA and the resultant methanol removed by distillation. Once 32 g of methanol have passed over, the reaction mixture is washed with weakly alkaline water, the organic phase separated and dried over Na2SO4. After fractionation, 160 g (93%) of 2,4-bis(chloromethyl)-1,3-dioxolane are obtained. Bp.: 98° C. (1500 Pa); IR: 1191, 1049, 1007 cm−1 (acetal); MS: m/e=169 (M−1), 140, 123, 121, 105, 93, 77, 75, 63, 57.
Reaction SMILES: [C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]([CH2:21][C:22]2[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=2)[CH2:25][NH:26]C(=O)OC(C)(C)C)[S:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[C:13]=2[OH:20])(=[O:11])=[O:10])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][CH2:25][C:24]1[CH:23]=[C:22]([CH:36]=[CH:35][CH:34]=1)[CH2:21][N:8]([CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:2][CH:3]=1)[S:9]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[C:13]=1[OH:20])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a solution of tert-butyl 3-((N-(biphenyl-4-ylmethyl)-3,5-dichloro-2-hydroxyphenylsulfonamido)methyl)benzylcarbamate (2.77 g, 4.41 mmol) in CH2Cl2 (15 mL) at rt was added TFA (6.8 mL, 88.0 mmol). The reaction mixture was stirred at rt for 4 h. It was concentrated and the residue was diluted with ethyl acetate and saturated aq NaHCO3 solution. The EtOAc layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give the product as a white solid (2.3 g, 96%). 1H NMR (DMSO-d6): δ 8.30 (bs, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.59 (s, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 7.32 (m, 2H), 7.29-7.18 (m, 5H), 7.10 (m, 1H), 4.43 (s, 4H), 3.93 (s, 2H), 3.32 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[CH3:8].[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[C:15]3=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: Cc1ccc(B(O)O)cc1C
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc([C@@H]3CCCN4CCS(=O)(=O)N=C34)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
A mixture of (3,4-dimethylphenyl)boronic acid (802 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg) and powdered 4A MS (5.00 g) in MeCN (18 ml) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (40.0 mg) as a white solid.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:42]1[C:47]2[NH:48][CH:49]=[CH:50][C:46]=2[C:45]([N:51]2[CH2:56][CH2:55][CH2:54][CH:53]([NH2:57])[CH2:52]2)=[N:44][CH:43]=1>CN(C=O)C.O.CCOC(C)=O>[N:42]1[C:47]2[NH:48][CH:49]=[CH:50][C:46]=2[C:45]([N:51]2[CH2:56][CH2:55][CH2:54][CH:53]([NH:57][C:9](=[O:11])[CH2:8][NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:52]2)=[N:44][CH:43]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: NC1CCCN(c2ncnc3[nH]ccc23)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CNc1ccccc1)NC1CCCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C

Procedure:
To a solution of 2-(phenylamino)acetic acid (37 mg, 0.25 mmol), EDCI (53 mg, 0.275 mmol), and HOBt (37 mg, 0.275 mmol) in DMF (1 mL) was DIEA (1.7 mL, 1.3 mg, 1.0 mmol) and 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (54 mg, 0.25 mmol). The solution was stirred at rt for several hours, diluted with water and EtOAc (1:1, 10 mL). The organic phase was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo to afford a residue which was purified by reverse phase chromatography C 18 column and 10% acetonitrile/water containing 0.1% TFA to afford example 2. 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.35 (s, 1H), 8.06 (d, J=6.8 Hz, 1H), 7.44 (s, 1H), 7.03˜7.70 (m, 3H), 6.52˜6.58 (m, 3H), 4.37 (d, J=12.7 Hz, 1H), 4.25 (d, J=12.2 Hz, 1H), 3.84 (s, 1H), 3.60 (m, 2H), 3.46 (m, 1H), 3.36 (m 1H), 1.87 (m, 2H), 1.61 (m, 2H). EIMS (m/z): calcd. for C19H22N6O (M++1) 351.2. found 351.2.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]([I:16])=[CH:15][C:3]=12.O.Cl>[OH-].[Na+]>[OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]([I:16])=[CH:15][C:3]=12
Reactant: CCOC(=O)c1cnc2sc(I)cc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc2sc(I)cc2c1O
Temperature: 25 °C
Yield: 93.6 %

Procedure:
Mercuric oxide (7.10 g) and iodine (8.32 g) are added portion-wise to a solution of ethyl 4-hydroxythieno[2,3-b]pyridine-5-carboxylate (J. Heterocyclic Chem. 1977, 14, 807) (5.22 g) in CHCl3 (90 mL). The reaction is stirred at rt for 18 h. The reaction mixture is filtered, and the solid is washed with CHCl3 (400 mL). The organic layer is washed with H2O (200 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified by column chromatography (CH2Cl2:heptane, 1:1). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 2.95 g (36%) of ethyl 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylate as a pale yellow solid. Ethyl 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylate (2.64 g) is suspended in 10% NaOH (21 mL) and heated to reflux. The reaction is stirred at reflux for 1 h and then cooled to rt. The reaction mixture is poured into H2O (80 mL). Conc. HCl is added until a precipitate forms, and 2.272 g (94%) of 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylic acid is isolated as a white solid. Carbonyldiimidazole (1.34 g) is added to a solution of 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylic acid (2.041 g) in DMF (58 mL). The reaction is heated to 60° C. and stirred for 18 h. The reaction mixture is cooled to rt, and 4-chlorobenzylamine (1.01 mL, 8.27) is added. The reaction is stirred at rt for 7 h. The reaction mixture is poured into 20% aqueous HOAc (180 mL), and the resulting white solid is filtered off. This material is recrystallized from methanol then toluene to yield 2.095 g (74%) of the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].O=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18].C(N(CC)CC)C>C(O)C>[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][OH:8])#[N:18]
Reactant: COC(=O)[C@H](N)CO
Reactant: N#CCCCCCC=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)[C@@H](CO)NCCCCCCC#N
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of D-serine methyl ester hydrochloride (0.91 g) in ethanol (18 mL) was added 7-oxoheptanenitrile (0.67 g) and triethylamine (0.6 mL) (see: Kubodera, N. et al, Heterocycles 1982, 19, 1285) and the mixture was stirred under N2 for 1 h. To the solution was then added Na(CN)BH3 (0.4 g) and the resultant cloudy suspension was further stirred under N2 for 1 h. The mixture was quenched with water and concentrated in vacuo and the residue diluted with ethyl acetate/saturated NaHCO3. The organic layer was separated and the aqueous layer extracted with ethyl acetate (3×). The organic layers were washed with water, brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by chromatography. Eluting with 5–10% (v) methanol in dichloromethane gave the desired product 2-1 (620 mg). 1H NMR (400 MHz, CDCl3): δ 3.78 (m, 1H), 3.77 (s, 3H), 3.59 (dd, 1H), 3.38 (dd, 1H), 2.72 (m, 1H), 2.53 (m, 1H), 2.36 (t, 2H), 1.70 (m, 2H), 1.55–1.35 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH3:14])[N+:12]=2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH2:14][Cl:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(Br)cc2)[n+]([O-])c1C
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCl
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A solution of 2-(4-bromophenyl)-4,5-dimethyl-oxazole-3-oxide (96.6 g, 0.36 mol) in CHCl3 (0.90 L) was treated dropwise with phosphorous oxychloride (61.1 g, 0.40 mol) allowing the reaction to exotherm and then stir at reflux for 30 min. The reaction was then cooled to rt and washed with water (2×1 L). The combined aqueous washes were back extracted with CH2Cl2 (2×400 mL). The organic layers were dried (MgSO4), and the solvent removed in vacuo to give crude product that was recrystallized from hot hexanes (300 mL), decanting the hot supernate away from a dark oily material. The remaining dark oil was agitated in additional hot hexanes (200 mL) and the combined supernates were cooled to 0° C. to crystallize the product which was isolated by filtration to give 74.2 g (72%) of 2-(4-bromophenyl)-4-(chloromethyl)-5-methyloxazole as a lime-green powder: Rf=0.39 in 20% EtOAc/hexanes; 1H NMR (500 MHz, CDCl3) δ 7.88-7.86 (m, 2H), 7.59-7.56 (m, 2H), 4.54 (s, 2H), 2.42 (s, 3H); 13C (125 MHz, CDCl3) δ 159.2, 146.9, 133.2, 132.0, 127.6, 126.1, 124.7, 37.1, 11.5; IR (KBr) 2970, 1633, 1599, 1481, 1401, 1258, 1117, 1008 cm−1; UV (EtOH) λmax 281 nm (ε 21349); HRMS (FAB) m/z calc'd for C11H1079BrClNO: 285.9634, found 285.9641; Anal. Calc'd for C11H9ClBrNO: C, 46.11; H, 3.17; N, 4.89; Cl, 12.37; Br, 27.88. Found C, 46.28; H, 3.07; N, 4.81; Cl, 12.36; Br, 27.88.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:38]1[C:46]2[C:41](=[C:42](B3OC(C)(C)C(C)(C)O3)[C:43]([F:47])=[CH:44][CH:45]=2)[CH:40]=[CH:39]1)(C(C)(C)C)(C)C>>[F:23][C:20]1([F:24])[CH2:21][CH2:22][N:17]([CH:15]2[CH2:16][N:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[N:7]=[C:2]([C:42]5[C:43]([F:47])=[CH:44][CH:45]=[C:46]6[C:41]=5[CH:40]=[CH:39][NH:38]6)[N:3]=[C:4]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:5]=4[N:11]=3)[CH2:14]2)[CH2:18][CH2:19]1
Reactant: FC1(F)CCN(C2CN(Cc3ccc4nc(Cl)nc(N5CCOCC5)c4n3)C2)CC1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(F)(F)CC4)C3)ccc2n1

Procedure:
4-(2-chloro-6-((3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 24.7 mg of 125 following reverse phase HPLC purification. MS (Q1) 538.3 (M)+
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].Cl.[O:25]([NH2:27])[CH3:26].N1C=CC=CC=1>C(O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[S:15][C:6]1[CH:5]=[C:4]([C:1](=[N:27][O:25][CH3:26])[CH3:2])[CH:14]=[CH:13][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Yield: 82.3 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (0.9 g), methoxylamine hydrochloride (0.21 g) and pyridine (0.2 g) in ethanol (15 ml) was refluxed for 4 hours. The mixture was concentrated under reduced pressure, and the residue was triturated with water to give a powder. The powder was recrystallized from ethanol to give 2'-(2,4-difluorophenylthio)-4'-[1-(methoxyimino)ethyl]methanesulfonanilide (0.8 g).
Reaction SMILES: C(N([CH2:6][C:7]1[CH:35]=[CH:34][C:10]2[C:11](=[O:33])[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:13][C:9]=2[CH:8]=1)CC)C.C([Cl:41])(=O)OCC.C(Cl)Cl>CC(O)C>[Cl:41][CH2:6][C:7]1[CH:35]=[CH:34][C:10]2[C:11](=[O:33])[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:13][C:9]=2[CH:8]=1
Reactant: CCN(CC)Cc1ccc2c(=O)n(C(c3ccccc3)(c3ccccc3)c3ccccc3)oc2c1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: O=c1c2ccc(CCl)cc2on1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.0 g of 6-(diethylamino)methyl-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one and 5.1 mL of ethyl chlorocarbonate were added to 60 mL of methylene chloride. This was then stirred for 3 hours at room temperature, and 140 mL of 2-propanol was added dropwise into the reaction mixture over a period of 30 minutes. The result was stirred for 2 hours at 5-15° C. and solids were filtered to obtain 16.6 g of 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one in the form of a pale yellowish-white solid.
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:9][C@H:10]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[NH2:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH:29]=[CH:28]1>>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]([NH:11][C@@H:10]([C:12]([N:14]3[CH2:15][CH2:16][CH:17]([CH:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)[CH2:18][CH2:19]3)=[O:13])[CH2:9][CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[O:37])[CH:34]=2)[CH:29]=[CH:28]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CN1CCC(C2CCN(C(=O)[C@H](N)CC3CCCCC3)CC2)CC1
Agent: Cl
Product: CN1CCC(C2CCN(C(=O)[C@@H](CC3CCCCC3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to that described in Method D-1, the titled compound was prepared from 1-(β-cyclohexyl-D-alanyl)-4-(1-methylpiperidin-4-yl)piperidine dihydrochloride and indole-6-carboxylic acid (65%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].BrC1SC(Br)=C(Cl)N=1.[BH4-].[Na+]>CO>[NH2:2][CH:3]([CH:9]([OH:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(N)C(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: Clc1nc(Br)sc1Br
Agent: [BH4-]
Solvent: CO
Product: CCOC(=O)C(N)C(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2-amino-3-oxo-3-(4-(trifluoromethyl)phenyl)propanoate hydrochloride (20.00 g, 64.17 mmol), was prepared as described by Singh, J., Tetrahedron Letters 34 (2), 211-214 (1993), was charged into a 500 mL round-bottomed flask and mixed with MeOH (160 mL). Sodium borohydride (3.641 g, 96.25 mmol) was added to the above mixture slowly at 0° C. The cooling bath was removed after the addition. The mixture was stirred at room temperature for 2 hours, and then filtered through a silica gel column in a funnel. The silica gel was washed with 10% MeOH (2.0M NH3)—CH2Cl2. The filtrate was concentrated in vacuo, and the crude product was triturated with 25% EtOAc-Hexane to provide the pure product as a white solid. LCMS (API-ES) m/z (%): 278 (M++H).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4](=[O:6])[OH:5].[F:17][CH2:18]C(OC(=O)CF)=O.C(N(CC)CC)C>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([CH2:18][F:17])=[O:9])[CH2:3][C:4](=[O:6])[OH:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C(CF)OC(=O)CF
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)CF
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of Boc-Asp-OH (8.11 mmol) and fluoroacetic anhydride (16.2 mmol) in benzene (30 ml) was treated with triethylamine (16.2 mmol) at room temperature. The catalyst 4-dimethylaminopyridine (0.41 mmol) was added to the solution and the reaction stirred for about 2 h at room temperature. About 100 ml benzene was added to the reaction mixture. The organic solution was washed with 1N HCl (2×50 ml), saturated NaHCO3 (2×50 ml), and saturated NaCl (2×50 ml), followed by drying over anhydrous MgSO4. The solvent was then removed by evaporation under reduced pressure. The resulting oil was applied to a 2.5×80 cm column of silica gel (60-200 mesh). The title compound was eluded with 2% methanol in chloroform.