Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)CN)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:32]4[CH:35]=[CH:36][CH:37]=[C:30]([CH2:29][N:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[CH:31]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: CN1CCN(Cc2cccc(CN)c2)CC1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Solvent: Oc1ccccc1
Product: CN1CCN(Cc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.177 g, 0.547 mmol), 3-(4-methyl-piperazin-1-ylmethyl)-benzylamine (0.100 g, 0.456 mmol) and phenol (1.00 g) were stirred at 130° C. for 1.5 hours. The reaction mixture was allowed to cool to r.t. The product was partly purified by flash chromatography using EtOAc, MeOH and TEA mixtures as eluent to give a yellow solid. The solid was washed with MeOH to give the product. Yield: 0.122 g (48%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.63 (d, 2H, J=8.52 Hz), 7.45 (s, 1H), 7.43 (d, 2H, J=8.52 Hz), 7.21-7.34 (m, 4H), 5.20 (s, 2H), 3.47 (s, 2H), 2.41 (bs, 8H), 2.25 (s, 3H). MS (ESI+) 464.93 (M+1H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[N:6][C:7]=1[Cl:8].[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16])([O-:12])=[O:11]>N1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>[Cl:8][C:7]1[C:2]([NH:1][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[N+:10]([O-:12])=[O:11])=[CH:3][C:4]([CH3:9])=[CH:5][N:6]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Cc1cnc(Cl)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of 5-amino-6-chloro-3-picoline (9.54 g, 66.9 mmol) in pyridine (200 mL) was added 2-nitrobenzoyl chloride (13.65 g, 73.6 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature (18 h). The dark mixture was then diluted with water (1500 mL) and sat. sodium bicarbonate solution was added until the pH reached 8. The precipitate was collected by filtration, rinsed with water (30 mL×3) and dried to afford N-(2-chloro-5-methylpyridin-3-yl)-2-nitrobenzamide as a pale solid (17.70 g, yield: 91%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:13]=[CH:12][C:5]2[CH2:6][C:7]([NH:9][C:10](=[O:11])[C:4]=2[CH2:3]1)=[O:8].[Cl:15][C:16]([Cl:22])([S:20]Cl)[CH:17]([Cl:19])[Cl:18]>C(N(CC)CC)C>[Cl:15][C:16]([Cl:22])([S:20][N:9]1[C:10](=[O:11])[C:4]2[CH2:3][C:2]([CH3:14])([CH3:1])[CH:13]=[CH:12][C:5]=2[CH2:6][C:7]1=[O:8])[CH:17]([Cl:19])[Cl:18]
Reactant: CC1(C)C=CC2=C(C1)C(=O)NC(=O)C2
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)C=CC2=C(C1)C(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(=O)C2
Reaction time: 4 h
Yield: 79.2 %

Procedure:
To a 200-ml methylene solution of 4,4-dimethylhomophthalimide (33.5 g) and 1,1,2,2-tetrachloroethyl sulfenyl chloride (42.2 g) at 0° C. was added dropwise 18.2 g triethylamine over 5 minutes. The mixture was stirred for 4 hours, washed with 200 ml water and dried (MgSO4). The solvent was evaporated and a brown oil was recovered, recrystallized in ethanol to yield 54 g (78%) tan solid, m.p. 112°-113° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:11][C:12]=1[C:13](=O)[NH:14][NH:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])=[O:17]>ClCCl>[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:11][C:12]=1[C:13]1[O:17][C:16]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[O:23][CH3:24])=[N:15][N:14]=1
Reactant: COc1ccsc1C(=O)NNC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccsc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Temperature: 100 °C
Yield: 23 %

Procedure:
TBTU (160.4 mg, 0.4995 mmol) and Et3N (33.70 mg, 46.42 μL, 0.3330 mmol) were added to a solution of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (100 mg, 0.3330 mmol) and 3-methoxythiophene-2-carboxylic acid (52.67 mg, 0.3330 mmol) in CH2Cl2 (2.000 mL) and the resulting solution stirred at room temperature for 72 h. The reaction mixture was diluted with dichloromethane (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (3×5 mL), and the combined organic extracts dried over MgSO4, filtered and concentrated in vacuo to leave 4-[5-amino-6-[[(3-methoxythiophene-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide as a yellow oil. POCl3 (1.788 g, 1.087 mL, 11.66 mmol) was added to 4-[5-amino-6-[[(3-methoxythiophene-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide and the resulting mixture heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and ice/water added carefully with vigourous stirring between additions. The mixture was left to stir at room temperature for 20 min and then diluted with dichloromethane (10 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (2×5 mL) and combined organics dried over MgSO4 and concentrated in vacuo. Solid obtained is re-dissolved in CH2Cl2 and purified by column chromatography on the ISCO column companion system (12 g column, 0-5% MeOH/ CH2Cl2). Product fractions were combined and concentrated in vacuo. This was purified further by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The product fractions were combined and freeze dried to give the product as a yellow solid (33.0 mg, 23% yield) 1H NMR (400 MHz, DMSO) d 2.98 (s, 3H), 3.01 (s, 3H), 4.07 (s, 3H), 7.30 (d, 1H), 7.56 (d, 2H), 7.70 (br s, 2H), 7.96 (d, 1H), 8.14 (d, 2H) and 8.97 (s, 1H) ppm; MS (ES+) 423.19
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]2[CH:25]=[CH:24][C:12]([C:13]([NH:15][C@H:16]([C:21](O)=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])=[C:11]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]=2)[CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:44][S:45]([NH:48][C:21](=[O:22])[C@H:16]([CH2:17][CH2:18][S:19][CH3:20])[NH:15][C:13](=[O:14])[C:12]1[CH:24]=[CH:25][C:9]([CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:47])=[O:46]
Reactant: CS(N)(=O)=O
Reactant: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1)C(=O)NS(C)(=O)=O
Temperature: 47.5 °C
Reaction time: 8 h

Procedure:
A solution in THF (5 mL) of [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]methionine (143 mg, 0.32 mmol), prepared as in Example 235, and carbonyldiimidazole (136 mg, 0.84 mmol) was stirred overnight at 45-50° C. A 1.6 mL aliquot of the reaction mixture was removed and to it was added methanesulfonamide (78 mg, 0.82 mmol) and DBU (0.12 mL, 0.80 mmol) and the mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between ethty acetate and pH 4 water. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographyl on silica gel (98.5:1.5:0.5 chloroform-methanol-acetic acid) gave [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]methionine methylsulfonyl amide. (31 mg after azeotroping and lyophilization). 1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, 1H), 8.39 (d, 1H), 8.18 (d, 1H), 7.50 (m, 4H), 7.36 (m, 6H), 5.28 (s, 2H), 4.27 (m, 1H), 3.21 (s, 3H), 2.20 (t, 2H), 2.02 (s, 3H), 1.81 (m, 2H). MS (APCI) m/e 514 (M+H)+. Anal calcd for C25H27N3O3S2.1.25H2O: C, 56.01; H, 5.55; N, 7.84. Found: C, 55.72; H, 5.08; N, 8.18.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][CH2:20][C:21](O)=O>C(OCC)(=O)C>[CH3:16][C:14]([CH3:15])([OH:17])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:21]1[CH2:20][O:19][CH3:18]
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Reactant: COCC(=O)O
Solvent: CCOC(C)=O
Product: COCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 170 °C
Yield: 9.9 %

Procedure:
3-Amino-4-(2-hydroxy-2-methylpropylamino)quinoline (7.5 g, 32 mmol) was combined with methoxyacetic acid (7.5 mL, 97 mmol) and heated at about 170° C. for about 3 hours. The resulting solid residue was dissolved in ethyl acetate (150 mL). The ethyl acetate solution was extracted twice with 0.2 N sodium hydroxide, washed with water, dried over magnesium sulfate, treated with activated charcoal and then concentrated to a volume of about 50 mL. Hexane was added to the ethyl acetate and the resulting precipitate was collected and dried to provide 0.9 g of the desired product as a crystalline solid, m.p. 145-148° C. Analysis: Calculated: %C, 67.3; %H, 6.7; %N, 14.7; Found: %C, 67.2; %H, 6.6; %N, 14.6.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[NH:9][C:8]([O:19][CH3:20])=[N:7][C:6]=1[CH2:21][O:22][CH3:23])=[O:4].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])[C:8]([O:19][CH3:20])=[N:7][C:6]=1[CH2:21][O:22][CH3:23])=[O:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)NC(OC)=N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Yield: 100.2 %

Procedure:
To a well stirred solution of (+)-5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine (1.167 g, 3.576 mmol) and 4-(N,N-dimethylamino)pyridine (0.655 g, 5.364 mmol) in CH2Cl2 (20 mL) was added powdered 4-nitrophenyl chloroformate (0.937 g, 4.65 mmol) at room temperature. Solvent was evaporated and the residue was purified by column chromatography on silica gel using hexanes/EtOAc (7/3%) as the eluent to give (−)-5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-diflurophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (1.761 g, 100%) as a viscous oil. [α]D=−335.3 (c=1.0 g in 100 mL CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:32])[C:30]#[CH:31].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:30]([C:29]#[CH:32])[CH3:31])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][N:15]=1
Reactant: C#CC(C)Br
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)Oc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
First, 150 mg of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357) was dissolved in 0.90 ml of N,N-dimethylformamide, to which 92 mg of potassium carbonate and 65 mg of 3-bromo-1-butyne were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 159 mg (yield, 92%) of 3-{2,4-dichloro-5-(3-butyn-2-yloxy)phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-371).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:9]([CH3:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: CCC(=O)c1ccc(C)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)C(C)Br)cc1

Procedure:
14.8 g (0.1 mol) of 4'-methylpropiophenone are introduced into 100 ml of chloroform, in the presence of a small amount of finely ground aluminium chloride, and a solution of 15.9 g (0.1 mol; 5 ml) of bromine, in 20 ml of chloroform is added dropwise whilst cooling with an ice bath. The mixture is left to react overnight at ambient temperature. It is then filtered, the solvent is evaporated off from the filtrate and the crystalline residue is washed with diethyl ether. 21.5 g of crystals are collected.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][CH:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[S:17])[NH:13][C:12]1=[O:36])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[C:38]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)(=[O:41])[CH:39]=[O:40]>C1C=CC=CC=1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][CH:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=2)=[O:23])=[S:17])[N:13]([CH:39]([OH:40])[C:38]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=2)=[O:41])[C:12]1=[O:36])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: c1ccccc1
Product: CC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 74.7 %

Procedure:
A mixture of 230 mg (0.40 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-[1-methyl-2-p-nitrobenzyloxycarbonylaminoethylthio(thiocarbonyl)]thioazetidin-2-one, 182 mg (0.80 mmole) of p-nitrobenzyl glyoxylate hydrate and 5 ml of benzene was heated under reflux for 10 hours. After completion of the reaction the solvent was distilled off and the resulting residue was subjected to column chromatography through 10 g of silica gel eluted with a 7-10% v/v solution of ethyl acetate in benzene to afford 234 mg (yield 75%) of the desired product as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(Cl)Cl.[F:51][C:52]([F:56])([CH3:55])[CH2:53]O>>[F:51][C:52]([F:56])([CH3:55])[CH2:53][O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][CH:15]=1)[NH:11][C:9]([C:6]1[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)=[O:10]
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Reactant: CC(F)(F)CO
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCC(C)(F)F)[nH]n1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (15.0 mg, 32 μmol), HOBt (12.8 mg, 95 μmol) and EDC (16.8 μL, 95 μmol) were combined in DCM (121 μL, 1.9 mmol) and stirred for 10 minutes. 2,2-Difluoropropanol (24.3 mg, 253 μmol) was added and the resulting mixture was stirred at room temperature until the reaction was complete (≈48 hours). The mixture was evaporated under reduced pressure and the product was purified (reverse phase column) to yield the title compound (13.8 mg, purity 96%) as a TFA salt. MS m/z [M+H]+ calc'd for C25H24ClF3N4O5, 553.14. found 553.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Clc1cccc(I)c1
Product: Clc1cccc(-n2ccc3ccc(Cl)cc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-chloro-3-iodobenzene: ESMS m/e: 261.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C(F)(F)F)ccc3N2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.47 mmol) in pyridine (74 mg, 0.94 mmol) and dichloromethane (2 mL) at 0° C. was added dropwise a solution of ethanesulfonyl chloride (90 mg, 0.70 mol) in dichloromethane (1 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford ethanesulfonic acid [3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (143 mg, 74.1%) as a white solid. MS (ESI+APCI) M+1=413.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:5][N:4]=1.[N:21]1([CH2:30][C:31](O)=[O:32])[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]=[CH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][N:18]([C:31](=[O:32])[CH2:30][N:21]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[CH:7][N:8]=1
Reactant: COc1ncc(-c2ccccc2N2CCNCC2)cn1
Reactant: O=C(O)Cn1ccc2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ncc(-c2ccccc2N2CCN(C(=O)Cn3ccc4cccnc43)CC2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To 2-methoxy-5-(2-piperazin-1-yl-phenyl)-pyrimidine (7.4 g, 27.37 mmol) dissolved in dichloromethane (100 mL) is added pyrrolo[2,3-b]pyridin-1-yl-acetic acid (4.82 g, 27.37 mmol), TBTU (8.79 g, 27.37 mmol), and DIPEA (14.66 mL, 82.12 mmol). The reaction is stirred for 16 h at ambient temperature. The product is purified on a 100 g Biotage SNAP column with 40% EtOAc in hexanes to provide the title compound (8.3 g, 19.37 mmol, 71% yield).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](Cl)=[C:21]([F:26])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1.CS(C)=O>CN(C=O)C.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]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[C:21]([F:26])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Cl)c(F)c3)nc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)c(F)c3)nc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-chloro-3-fluorophenyl)acetamide 168-2 (80 mg, 0.2 mmol) and 2-methyl-4-(tributylstannyl)pyridine (78 mg, 0.2 mmol) in DMF (0.6 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33 mg, 0.04 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was diluted into DMSO and purified by reverse-phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-fluoro-4-(2-methylpyridin-4-yl)phenyl)acetamide 168 as white solid. MS m/z 448.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.57 (s, 1H), 8.52 (d, 1H), 8.04 (s, 1H), 7.93 (d, 1H), 7.59 (m, 1H), 7.44-7.29 (m, 5H), 3.77 (s, 2H), 3.58 (b, 2H), 3.14 (b, 2H), 3.08 (b, 2H), 2.55 (s, 2H), 2.51 (s, 3H), 2.04 (s, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:42]2[C:41](=[CH:43][CH2:44][CH2:45][OH:46])[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.[CH2:51]([O:53][CH:54]([CH2:60][C:61]1[CH:66]=[CH:65][C:64](O)=[CH:63][CH:62]=1)[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH3:52]>C1COCC1.O>[CH:32]1[C:42]2[C:41](=[CH:43][CH2:44][CH2:45][O:46][C:64]3[CH:63]=[CH:62][C:61]([CH2:60][CH:54]([O:53][CH2:51][CH3:52])[C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:66][CH:65]=3)[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCC=C1c2ccccc2COc2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCC=C2c3ccccc3COc3ccccc32)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.235 ml, 1.49 mmol) was added at 0° C. to a stirred solution of triphenylphosphine (0.392 g, 1.49 mmol) and 3-(6H-dibenzo[b,e]oxepin-11-ylidene)-1-propanol (0.252 g, 1.0 mmol) in dry THF (5 ml) and the mixture stirred for 5 min. A solution of ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.356 g, 1.49 mmol) in dry THF (5 ml) was then added, the mixture allowed to warm to room temperature, and stirring continued for 18 h. The resulting mixture was treated with water (50 ml), and the products extracted into dichloromethane (4×50 ml). The extracts were combined, washed with brine, dried (Na2SO4) and evaporated to an orange gum. This was then purified by column chromatography on silica gel (20% Et2O in petroleum eluent) to give the title compound as an inseparable 4:1 mixture of E and Z double-bond isomers, as a pale yellow gum; 0.252 g (53%).