Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f13) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.NC[CH2:19][CH2:20][C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:7]1(=[O:16])[N:6]([CH2:1][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O
Yield: 63 %

Procedure:
N-Carboethoxyphthalimide (10.96 g) was added on one portion to a vigorously stirred solution of 4-aminobutanoic acid (5.16 g) and sodium carbonate (5.35 g) in water (150 ml) at RT. The mixture was stirred until essentially all the solid material had dissolved (30 min), then it was filtered. The filtrate was acidified to pH1 with 6N aqueous hydrochloric acid (ca. 22 ml) and the white precipitate was collected by filtration and washed thoroughly with water (150 ml). The solid was dried in air, then in vacuo to give the title compound as a colourless solid (7.35 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9](=[O:17])[N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:11][C:3]=12.Cl.Cl.[CH2:20]([C:22]1[N:23]=[C:24]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:25]([CH2:27][CH2:28][OH:29])[CH:26]=1)[CH3:21].C(N(C(C)C)CC)(C)C>CO>[CH2:20]([C:22]1[N:23]=[C:24]([CH:30]2[CH2:31][CH2:32][N:33]([C:2]3[N:7]=[CH:6][N:5]=[C:4]4[NH:8][C:9](=[O:17])[N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:11][C:3]=34)[CH2:34][CH2:35]2)[N:25]([CH2:27][CH2:28][OH:29])[CH:26]=1)[CH3:21]
Reactant: O=C1Nc2ncnc(Cl)c2CN1CC(F)(F)F
Reactant: CCc1cn(CCO)c(C2CCNCC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCc1cn(CCO)c(C2CCN(c3ncnc4c3CN(CC(F)(F)F)C(=O)N4)CC2)n1
Temperature: 150 °C
Yield: 140.7 %

Procedure:
Add 5-chloro-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.28 g, 1.05 mmol), 2-(4-ethyl-2-(piperidin-4-yl)-1H-imidazol-1-yl)ethanol dihydrochloride (0.38 g, 1.3 eq), methanol (15 mL) and diisopropylethylamine (0.91 mL, 5.0 eq) into a 20 mL microwave vial. Seal the tube and heat in a microwave reactor to 150° C., for 1 hour. Filter through silica gel, eluting with 10% ammonia-methanol/dichloromethane. Concentrate the filtrate in vacuo. Purify by silica gel chromatography, eluting with 3:1 ethyl acetate/methanol, to give the title compound as a yellow foam (0.67 g, 70%). MS (ES) m/z=454 [M]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][S:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O.[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[OH:38].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH:38][C@@H:33]1[CH2:34][CH2:35][CH2:36][CH2:37][C@@H:32]1[NH:31][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[N:27][C:19]=1[O:18][C:17]1[CH:28]=[CH:29][CH:30]=[C:15]([S:14][CH3:13])[CH:16]=1
Reactant: N[C@H]1CCCC[C@H]1O
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncccc2C(=O)N[C@H]2CCCC[C@H]2O)c1
Reaction time: 18 h
Yield: 48.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (293 mg, 1.53 mmol) was added to a solution of 2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.765 mmol), (1R,2S)-2-aminocyclohexanol hydroformate [8151/195/2] (123 mg, 0.765 mmol), 1-hydroxybenzotriazole (114 mg, 0.842 mmol) and triethylamine (430□l, 3.10 mmol) in dimethylformamide (5 ml) under nitrogen at room temperature. The reaction was stirred for 18 h and partitioned between diethyl ether (25 ml) and water (25 ml). The organic phase was washed with brine (30 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (50:50 as eluant) to give N-[(1 S,2R)-2-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (133 mg) as a gum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8]C(C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[K+].[Br-].[C:13]([OH:16])(=[O:15])[CH3:14]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:14]([C:13]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)c1ccc([N+](=O)[O-])cc1
Yield: 86.5 %

Procedure:
The oxidation of 300 g of p-nitrotoluene in 2500 ml of glacial acetic acid, in the presence of 4 g KBr and 15 g Co(OA)2 . 4H2O, at a reaction temperature of 185° C and a reaction time of 3 hours, gave a yield of 86.5% of p-nitrobenzoic acid. The absorption of oxygen began at 165° C. During the reaction CO2 was detected qualitatively in the residual gas. After the addition of 500 ml of benzene, 103 g of water (240% of the theory) was distilled azeotropically from the mother liquor.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:8][CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
NaH (60% in mineral oil, 1.2 g, 30 mmol) was added to an ice-cooled solution of (4-hydroxy-phenyl)-phenyl-methanone (5 g, 25.2 mmol) in DMF (25 mL). The resulting mixture was stirred for 20 minutes at room temperature (r.t.). Benzyl bromide (6.1 mL, 50 mmol) was added at 0° C. The reaction temperature was raised to r.t. after 1 h and thereafter stirred for additional 2 h. Water (20 mL) was added and the aqueous phase was extracted with dichloromethane (2×30 mL). The combined organic phase was concentrated and purified by flash chromatography (eluent: 100% dichloromethane). Yield: 7.0 g, 96% of 1. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J=8.4 Hz, 2H), 7.77 (d, J=7.2 Hz, 2H), 7.58-7.52 (m, 1H), 7.50-7.32 (m, 7H), 7.03 (d, J=8.4 Hz, 2H), 5.17 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]([NH:19][CH3:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[C:25](OC=O)(=[O:27])C.C(OC(=O)C)(=O)C>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N:8]([NH:19][CH2:20][CH:25]=[O:27])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Reactant: CC(=O)OC=O
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3NCC=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Fluoro-methylamino-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (Example 1) (2.7 g) was added to mixed formic-acetic anhydride prepared from 3.9 g of 96% formic acid and 8.3 g of acetic anhydride. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The solid residue was dissolved in 50 ml of water and the solution made basic with pyridine. The solid product was collected by filtration and recrystallized from acetonitrile to give 2.0 g of 6-fluoro-1-(N-formylmethylamino)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, cream-colored powder, m.p. 252°-253° C. (decompn.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([S:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[O:17])=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:13][C:12]=2[CH:31]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([S:16]([C:15]2[C:11]3[CH:10]=[CH:9][C:8]([CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:31][C:12]=3[S:13][C:14]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1sc2cc(CO)ccc2c1S(=O)c1cccc(OC)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc2cc(COS(C)(=O)=O)ccc2c1S(=O)c1cccc(OC)c1
Yield: 66.2 %

Procedure:
Methanesulfonyl chloride (0.043 ml, 0.55 mmol) was added to a stirred solution of ethyl 6-(hydroxymethyl)-3-[(3-methoxyphenyl)sulfinyl]benzo[b]thiophene-2-carboxylate (Preparation 17, 195 mg, 0.5 mmol) and N-ethyl-N,N-diisopropylamine (0.1 ml, 0.55 mmol) in dichloromethane (3 ml) at 0° C. After 3 hours the solution was washed twice with water, dried (magnesium sulfate), and the solvent removed under reduced pressure. The residue was crystallised from diethyl ether to give the title compound as a colourless solid (155 mg).
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[S:10]([CH3:13])(=[O:12])=[O:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:3])=[O:21])[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)S(C)(=O)=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCC(O)CCCN(CCCCCCC(=O)OC)S(C)(=O)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoic acid (10.8 g., 0.03 mole) (Example 1, Step B) in ether (50 ml.). The resulting solution is allowed to stand at room temperature for 4 hours. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoate as a viscous oil.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.C[Li].[CH2:17](OCC)C.[Cl-].[NH4+]>O1CCCC1>[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)(=[O:5])[CH3:17]
Reactant: CCOCC
Reactant: CCOC(=O)c1cc2ccoc2cn1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc2ccoc2cn1
Temperature: -30 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
5-Ethoxycarbonylfuro[2,3-c]pyridine obtained in Example 2(3.82 g, 20.0 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −30° C. To the cooled solution, 22.0 mL (22.0 mol) of 1.0 M solution of methyllithium/diethyl ether was added, and the solution was stirred for 2 hours at the same temperature, the reaction mixture was then poured into 100 mL of 5% ammonium chloride aqueous solution which had been cooled on ice, and the product was extracted twice with 100 mL of ethyl acetate. After washing with 100 mL of saturated sodium bicarbonate aqueous solution and 100 mL of saturated saline water, the extract was concentrated to give 3.12 g of crude product. This product was purified by column chromatography on silica gel, giving 2.48 g (77.0% yield) of 5-acetylfuro[2,3-c]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:25]=[O:26])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1.[S:28]([CH2:38][N+:39]#[C-:40])([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].[C-]#N.[Na+].C1COCC1>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:25]3[O:26][CH:40]=[N:39][CH:38]3[S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1
Reactant: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)C2N=COC2c2cc3c(ncn3CCS(C)(=O)=O)c(F)c2Nc2ccc(Br)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde 10z (0.050 g, 0.107 mmol) is suspended in EtOH (0.5 mL) under N2 and tosylmethyl isocyanide (0.020 g, 0.105 mmol) is added followed by catalytic NaCN (˜1 mg). After 2 hours, 2 mL THF is added to assist with solubility. After stirring for 16 hours at room temperature, a second equivalent of tosylmethyl isocyanide (0.020 g, 0.105 mmol) is added. After 8 hours, the reaction mixture is concentrated under reduced pressure and used as is in the next reaction: LC/MS ESI (+) m/z 671, 669 (M+ Br pattern) detected.
Reaction SMILES: C(O)(=O)C.[CH2:5]([NH:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[C:13]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][C:24]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:12][N:11]=1)=[O:9])[CH3:6].[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CO>[CH2:5]([NH:7][C:8]([C:10]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:19][CH:20]=2)=[C:13]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:25][C:24]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:12][N:11]=1)=[O:9])[CH3:6]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Reactant: C1COCCN1
Solvent: CO
Solvent: CC(=O)O
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Acetic acid (0.37 ml, 6.44 mmol) was added dropwise to a mixture of 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (730 mg, 1.29 mmol), morpholine (0.225 ml, 2.58 mmol), 3A powdered molecular sieves (730 mg) and MeOH (21 ml). This was left to stir overnight under N2. The mixture was then evaporated in vacuo and the resultant crude partitioned between CH2Cl2 (3×40 ml) and sat. NaHCO3 solution (40 ml). The combined, dried (Na2SO4) organics were evaporated in vacuo to give crude 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (810 mg) as a yellow solid, LC/MS: RT=2.365 min. 638.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2].[F:12][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([F:12])=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c[nH]1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(F)[nH]1
Temperature: 25 °C

Procedure:
4-Fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g, 10.0 mmol) is dissolved in acetonitrile (10 ml), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™, 3.54 g, 10.0 mmol) is added and the mixture is irradiated in a Biotage Initiator microwave synthesizer for 5 minutes at 70° C. The reaction mixture is allowed to cool to room temperature and partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 4,5-difluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 1.78 (C), [M+H] 176; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 12.93 (s, 1H), 6.67 (d, J=4.5 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl.[CH3:23][N:24](C)[CH2:25][CH2:26][CH2:27]Cl>CN(C)C=O.C(OCC)(=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([N:8]2[CH2:27][CH2:26][CH2:25][N:24]([CH3:23])[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]2=3)=[O:19])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=C(Nc1cccnc1Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc21
Temperature: 0 °C
Yield: 20.7 %

Procedure:
To a solution of 2-chloro-3-(4-nitrobenzoyl)aminopyridine (1.93 g) in N,N-dimethylformamide (13 ml) was added sodium hydride (60 % in oil, 585 mg) and the solution was stirred at 0° C. for ten minutes. 3-Dimethylaminopropyl chloride hydrochloride (1.16 g) was added to the solution and the mixture was stirred for 3 hours at 150° C. The solution was diluted with ethyl acetate and the solution was washed with successively with water, saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (80 g, ethyl acetate:n-hexane =1:3) to give 1-(4-nitrobenzoyl)-5-methyl-2,3,4,5-tetrahydropyrido [3,2 -b][1,4]diazepine (450 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][N:3]=1.[Cl:23][C:24]1[S:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.O1CCOCC1>[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=4)[CH:9]=3)[NH:4][N:3]=2)=[O:30])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3[nH]nc(N)c3c2)o1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc3[nH]nc(NC(=O)c4ccc(Cl)s4)c3c2)o1

Procedure:
300 mg of tert-butyl 5-(3-amino-1H-indazol-5-yl)furan-2-carboxylate, 199 mg of 5-chlorothiophene-2-carbonyl chloride and 8 mg of 4-(dimethylamino)pyridine are stirred at 90° C. for 24 hours in 2 ml of pyridine and 100 μl of dioxane. The reaction mixture is evaporated, and the residue is purified by column chromatography. Yield: 260 mg (58%) of tert-butyl 5-{3-[(5-chlorothiophene-2-carbonyl)amino]-1H-indazol-5-yl}furan-2-carboxylate.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]([F:13])([CH:10]([F:12])[F:11])[CH2:8][OH:9].Cl>N1C=CC=CC=1>[C:2](=[O:3])([O:9][CH2:8][C:7]([F:13])([F:6])[CH:10]([F:12])[F:11])[O:4][CH3:5]
Reactant: OCC(F)(F)C(F)F
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)OCC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Methyl chloroformate (130 mL, 159 g, 1.68 mol) was added slowly over a period of 3 h to a solution of 2,2,3,3-tetrafluoropropanol (132 g, 1.00 mol) in pyridine (300 mL, anhydrous) at −10° C. to 0° C. with magnetic stirring. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was mixed with 5% HCl (500 mL) and approximately 50 g of ice, and the resulting mixture was extracted three times with 300 mL portions of ether. The combined organic layer was washed three times with 100 mL portions of 5% HCl, followed by two washes with 100 mL portions of 5% sodium carbonate. The organic phase was then dried over anhydrous sodium sulfate. Ether was removed by rotary evaporation. The crude product (approximately 200 g) was distilled, yielding 166 g (87% yield) of pure methyl 2,2,3,3-tetrafluoropropyl carbonate, also referred to herein as “FS-C”. NMR analysis data were consistent with the literature values (U.S. Pat. No. 5,659,062).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=O)=[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:5]2=[CH:4][CH:3]=1.[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].[BH4-].[Na+].Cl>CO.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:11]=1[CH2:12][NH:17][C:16]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:15]=1[F:14]
Reactant: Nc1ccc(F)cc1F
Reactant: O=Cc1c(O)ccc2c1CCCO2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1ccc2c(c1CNc1ccc(F)cc1F)CCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.7 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-5-carboxaldehyde (299 mg, 1.68 mmol) and 2,4 -difluoroaniline (219 mg, 1.68 mmol) in methanol (8 mL) was heated to reflux for 20 minutes during which time the intermediate Schiff's base crystallized, and, after cooling to room temperature, was collected by filtration and dried. The isolated Schiff's base (175 mg, 36%) was suspended in methanol (8 mL) and sodium borohydride (25 mg, 0.66 mmol) was added. The mixture was stirred at room temperature for 5 minutes, poured into water (50 mL) and carefully neutralized (pH=7) with 2.5 N HCl. The product was collected by filtration and dried to afford 6-hydroxy-5-(2,4-difluorophenyl)aminomethyl-3, 4-dihydrobenzopyran, (170 mg, 96.6%), m.p. 120°-121° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1)#[N:2].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[NH2:18]>>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([NH:18][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[OH:12])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=1
Reactant: N#Cc1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: N#Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 16.6 %

Procedure:
Using 5-cyanosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.