Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([B:23]2[O:27][C:26]([CH3:29])(C)C(C)(C)[O:24]2)=[C:17]([CH:20]=[CH:21][CH:22]=1)C=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:32](C)([O-:34])=[O:33]>O.C1COCC1>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]2[B:23]([OH:24])[O:27][CH:26]([CH2:29][N+:32]([O-:34])=[O:33])[C:17]=2[CH:20]=[CH:21][CH:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: CC1(C)OB(c2c(C=O)cccc2OCCCOCc2ccccc2)OC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To an ice cold solution of NaOH (0.68 g, 0.017 mol) in 10 ml of water was added a solution of compound D (6.8 g, 0.017 mol) dissolved in 5 ml of THF. After 15 minutes, nitromethane (0.93 ml, 0.017 mol) was added drop by drop and the content stirred at RT overnight. The THF was evaporated under reduced pressure and the contents acidified to pH-3 with 2N HCl. The aqueous layer was extracted with EtOAc several times, and the combined ethyl acetate layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of 10% EtOAc/hexane to 30% EtOAc/hexane) provided 3.7 g (55% yield) of E [7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol] 3.7 g.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[Cl:8][C:9]1[C:17]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23]>O>[Cl:8][C:9]1[C:17]([S:18](=[O:19])(=[O:20])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Reactant: CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: To the stirred solution 7.3 g of n-butylamine, 8 g of sodium hydroxide in 200 ml of water, 30 g of 4-chloro-5-chlorosulfonyl-3-nitrobenzoic acid are added portionwise while keeping the temperature between 0° and 5°. After 1/2 hour the mixture is allowed to warm to room temperature for 2 hours. The supernatant solution is filtered, the filtrate combined with 25 ml of 2N of hydrochloric acid, the precipitate formed collected and recrystallized from aqueous ethanol, to yield the 4-chloro-3-nitro-5-n-butylsulfamoylbenzoic acid melting at 199°-201°.
Reaction SMILES: C([C@H]1CSC(=O)N1[C:14]([C@@H:16]([C@@H:29]([OH:45])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)[CH2:17][N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=[N:19]1)=[O:15])C1C=CC=CC=1.[OH:46]O.O.[OH-].[Li+]>O1CCCC1.O.O>[F:44][C:41]1[CH:40]=[CH:39][C:38]([C:35]2[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][C@@H:29]([OH:45])[C@H:16]([CH2:17][N:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[N:20]=[N:19]3)[C:14]([OH:15])=[O:46])=[CH:33][CH:34]=2)=[CH:43][CH:42]=1
Reactant: OO
Reactant: O=C1SC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cn1nnc2ccccc2c1=O)[C@@H](O)CCc1ccc(-c2ccc(F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](Cn1nnc2ccccc2c1=O)[C@H](O)CCc1ccc(-c2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of the compound obtained from step f above (0.18 g) in tetrahydrofuran:water (3:1, 10 mL), aqueous hydrogen peroxide solution (30%, 0.15 mL) was added at 0° C., followed by the addition of lithium hydroxide monohydrate (17.6 mg) in water (2 mL). The reaction mixture was stirred at 0° C. until the completion of the hydrolysis. The reaction mixture was concentrated and the residue was extracted with ethyl acetate. The aqueous layer was acidified with sodium hydrogen sulphate and extracted with ethyl acetate. The combined layers were washed with water and brine, and dried over anhydrous sodium sulphate. The solvents were evaporated under reduced pressure and the crude residue was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as eluant to afford the title compound (0.075 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Si:5]1([CH3:19])[O:12][Si:11]([CH3:14])([CH3:13])[O:10][Si:9]([CH3:16])([CH3:15])[O:8][Si:7]([CH3:18])([CH3:17])[O:6]1.N1C=CC=CC=1.[F:26][C:27]([F:50])([C:31]([F:49])([F:48])[C:32]([F:47])([F:46])[C:33]([F:45])([F:44])[C:34]([F:43])([F:42])[C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])[C:28](Cl)=[O:29]>>[F:26][C:27]([F:50])([C:31]([F:48])([F:49])[C:32]([F:46])([F:47])[C:33]([F:44])([F:45])[C:34]([F:42])([F:43])[C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])[C:28]([O:1][CH2:2][CH2:3][CH2:4][Si:5]1([CH3:19])[O:12][Si:11]([CH3:14])([CH3:13])[O:10][Si:9]([CH3:16])([CH3:15])[O:8][Si:7]([CH3:18])([CH3:17])[O:6]1)=[O:29]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[Si]1(C)O[Si](C)(C)O[Si](C)(CCCO)O[Si](C)(C)O1
Solvent: c1ccncc1
Product: C[Si]1(C)O[Si](C)(C)O[Si](C)(CCCOC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)O[Si](C)(C)O1

Procedure:
A 25 mL round bottom flask equipped with a magnetic stirring bar and an addition funnel was charged with 4.0 g of (3-hydroxypropyl)heptamethylcyclotetrasiloxane (12 mmoles) and 1.0 g of pyridine (13 mmoles). The mixture was stirred and 5.0 g of perfluorooctanoyl chloride (12 mmoles) was added dropwise. After complete addition of the acid fluoride a gas chromatographic analysis indicated that essentially all of the acid chloride and most of the cyclosiloxane were consumed with one product as 96.5% of the mixture. The contents of the flask were filtered using a 0.45 micron syringe filter into a 50 mL 1-necked round bottom flask. The solids in the flask were washed with 2.5 mL of pentane and this suspension added to the syringe and filtered into the 50 mL flask. The solids in the syringe were washed with an additional 2.5 mL of pentane and filtered into the 50 mL flask. The contents of the flask were distilled at 82° C. and 0.04 mmHg to yield a fraction of [3-(perfluorooctanoyl)oxypropyl]-heptamethylcyclotetrasiloxane which corresponds to formula (I) wherein m is 1, n is 3, X is OC(O), and RF is a perfluorinated straight chain monovalent alkyl radical of 7 carbons atoms, or more specifically as shown in formula (VIII) below. ##STR9##
Reaction SMILES: FC(F)(S(O[C:17]1[CH:31]=[C:20]2[CH2:21][CH2:22][CH:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:19]2[N:18]=1)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[Cl:33][C:34]1[N:35]=[CH:36][N:37]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][C:40]=2[O:46][CH3:47])[CH:38]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CN1CCCN2CCCN=C12>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:33][C:34]1[N:35]=[CH:36][N:37]([C:39]2[CH:45]=[CH:44][C:42]([NH:43][C:17]3[CH:31]=[C:20]4[CH2:21][CH2:22][CH:23]=[C:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:19]4[N:18]=3)=[CH:41][C:40]=2[O:46][CH3:47])[CH:38]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: O=S(=O)(Oc1cc2n(n1)C(c1ccccc1)=CCC2)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CN1CCCN2CCCN=C12
Solvent: Cc1ccccc1
Product: COc1cc(Nc2cc3n(n2)C(c2ccccc2)=CCC3)ccc1-n1cnc(Cl)c1
Yield: 21 %

Procedure:
A mixture of 7-phenyl-4,5-dihydropyrazolo[1,5-a]pyridin-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (400 mg, 0.809 mmol, from AAH), 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (362 mg, 1.618 mmol, from step 2 of preparation A), tris(dibenzylideneacetone)dipalladium(0) (29.6 mg, 0.032 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (70.2 mg, 0.121 mmol), and 1-methyl-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (372 mg, 2.428 mmol) in toluene (5 mL) was microwaved in a biotage chemistry microwave at 160° C. for 2 h. The crude reaction mixture was loaded directly on to silica gel and purified using silica gel column chromatography (0-80% EtOAc/hexanes) to afford N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4,5-dihydropyrazolo[1,5-a]pyridin-2-amine (70 mg, 21% yield). LC-MS (M+H)+ 418.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.58 (dd, J=6.56, 1.37 Hz, 2 H) 7.49 (d, J=1.53 Hz, 1H) 7.43 (d, 0.1-2.44 Hz, 1 H) 7.34-7.40 (m, 3H) 7.02 (d, J=8.55 Hz, 1H) 6.99 (d, J=1.83 Hz, 1H) 6.53 (dd, J=8.55, 2.44 Hz, 1H) 6.31 (s, 1 H) 5.83 (s, 1 H) 5.47-5.52 (m, 1 H) 3.53 (s, 3 H) 2.96 (t, J=7.93 Hz, 2 H) 2.43-2.52 (m, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]=[C:12]([NH:14][C:15]2[N:16]=[C:17]([O:32][CH2:33][C@H:34]3[C@H:38]([CH3:39])[CH2:37][NH:36][CH2:35]3)[C:18]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:19]=3[N:20]=2)[CH:11]=[N:10]1.CCN(C(C)C)C(C)C.[C:49](Cl)(=[O:52])[CH:50]=[CH2:51]>C(Cl)Cl.C(Cl)Cl.CO>[CH3:39][C@H:38]1[C@H:34]([CH2:33][O:32][C:17]2[C:18]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:19]=3[N:20]=[C:15]([NH:14][C:12]3[CH:11]=[N:10][N:9]([CH3:8])[CH:13]=3)[N:16]=2)[CH2:35][N:36]([C:49](=[O:52])[CH:50]=[CH2:51])[CH2:37]1
Reactant: C[C@@H]1CNC[C@H]1COc1nc(Nc2cnn(C)c2)nc2c1ccn2COCC[Si](C)(C)C
Reactant: C=CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1C[C@@H](COc2nc(Nc3cnn(C)c3)nc3c2ccn3COCC[Si](C)(C)C)[C@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of the TFA salt of N-(1-methyl-1H-pyrazol-4-yl)-4-{[trans-4-methylpyrrolidin-3-yl]methoxy}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-2-amine (0.9 g, 1.61 mmol) in dry DCM (20 mL) were added DIPEA (1.25 g, 9.7 mmol) and acryloyl chloride (144.9 mg, 1.61 mmol) at rt. After the addition, the reaction mixture was stirred at rt for 1 hr. TLC(CH2Cl2/MeOH=10:1) showed the reaction was complete. The reaction mixture was diluted with DCM (10 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to yield the title compound (0.82 g, 100% yield) as a brown solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]Br.O>CO>[CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:25])[CH2:24][Br:26])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: BrBr
Solvent: O
Solvent: CO
Product: O=C(CBr)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of N-benzyl-2-nitro-N-(3-oxobutyl)benzenesulfonamide (compound F, 30 g, 83 mmol) in methanol (300 ml) was added bromine (4.69 ml, 91 mmol) in one portion at 20-25° C. Stirred for 20 hours (no bromine colour), water (20 ml) added, heated to reflux for 30 min, diluted with MeOH (100 ml). The solution was cooled to 30° C. with stirring, seeded with compound G, stirred at 25-30° C. for 5 min (crystallisation occurred), cooled to 15° C., aged for 1 hour. Crystals collected, washed with 2×15 ml of MeOH (20-25° C.), dried on air to give N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide (19.4 g, 44.0 mmol, 53.1% yield).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1>C(#N)C>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][CH2:4][CH2:3][N:9]3[CH2:8][CH2:7][CH2:6][CH2:15][CH:10]3[CH3:11])=[CH:7][CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: ClCCNc1ccnc2cc(Cl)ccc12
Agent: Cl
Solvent: CC#N
Product: CC1CCCCN1CCNc1ccnc2cc(Cl)ccc12

Procedure:
1.4 g from 2.5 g of N-(2-chloroethyl)-7-chloro-4-quinolinamine hydrochloride; colourless crystals from acetonitrile, m.p.: 133°-134° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH3:34])=[O:32])=[C:26]([Cl:35])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH3:34])=[O:32])=[C:26]([Cl:35])[CH:25]=1)#[N:7]
Reactant: CCNCC
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)cc1Cl
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)NC)c(Cl)c3)c2cc1C#N
Temperature: 60 °C

Procedure:
After adding tetrahydrofuran (3.0 ml) and diethylamine (1.50 ml) to N-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea (100 mg), the mixture was heated at 60° C. for 5 hours. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol) to obtain the title compound (75 mg) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C@H:10]([CH3:13])[CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C@H:10]([CH3:13])[CH2:11][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CCl)COc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-4-{[(2S)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH:12]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccccc1-c1ccccn1
Temperature: 80 °C
Yield: 50 %

Procedure:
This Example was carried out in the same manner as Example 1, except that 5.0 g (0.032 mol) of 2-chloro-phenyl boronic acid, 10.0 g (0.064 mol) of 3-bromopyridine, 150□ of tetrahydrofuran and 2M potassium carbonate solution (20□) were added and then 0.37 g (3 mol %) of palladium tetrakistriphenylphosphine [(pd(PPh3)4] was used as a catalyst. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 2-(2-chloro-phenyl)pyridine was isolated. The yield was 50%.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1O)=[O:2].[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([NH:16][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[N:1]=[O:2])[CH3:15]
Reactant: CCN
Reactant: O=Nc1c(O)ccc2ccccc12
Product: CCNc1ccc2ccccc2c1N=O

Procedure:
The starting 2-ethylamino-1-nitrosonaphthalene is prepared by reacting 1-nitroso-2-naphthol with ethylamine following the same procedure described in the second part of example 12.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1B1OC(C)(C)C(C)(C)O1)[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:13])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])=[CH2:9]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: C=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2ccc(C(=O)OC)cc2C)cc1[N+](=O)[O-]

Procedure:
4-Chloro-1-ethenyl-2-nitrobenzene (1.1406 g, 6.21 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.059 g, 7.46 mmol), 1,1bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.422 g, 0.621 mmol), cesium carbonate (4.25 g, 13.05 mmol) and THF (30 mL) were heated in an 80° C. oil bath overnight. Volatiles were removed under reduced pressure. The pot residue was taken up by dichloromethane and filtered. The filtrate was concentrated in vacuo to afford a dark solid. The resulting solid was purified by flash chromatography (SiO2, Biotage SNAP cartridge, silica gel, 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated a light orange solid as the titled compound. LCMS calc.=297.10. found=298.10 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:5](=[O:23])[C:6]2[O:22][CH2:21][CH2:20][C:7]=2[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:9]=1)[CH3:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(#N)C>[C:2]([C:4]1[C:5](=[O:23])[C:6]2[O:22][CH2:21][CH2:20][C:7]=2[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:9]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1nn(-c2cccc(C(F)(F)F)c2)c2c(c1=O)OCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)c2c(c1=O)OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 3-(1-hydroxyethyl)-1-[3-(trifluoromethyl)phenyl]-6,7-dihydrofuro[3,2-c]pyridazin-4(1H)-one (0.858 g) in acetonitrile (20 mL) was added Dess-Martin Periodinane (1.23 g) portionwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate to give the title compound (0.739 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[OH:30][CH2:31][CH2:32][NH:33][S:34]([C:37]1[S:38][C:39]([Cl:43])=[C:40]([NH2:42])[CH:41]=1)(=[O:36])=[O:35]>>[Cl:43][C:39]1[S:38][C:37]([S:34](=[O:36])(=[O:35])[NH:33][CH2:32][CH2:31][OH:30])=[CH:41][C:40]=1[NH:42][C:27]([C:26]1[CH:25]=[N:24][N:17]2[C:18]([C:20]([F:22])([F:23])[F:21])=[CH:19][C:14]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:13])[F:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[N:15][C:16]=12)=[O:28]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cc(S(=O)(=O)NCCO)sc1Cl
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cc(S(=O)(=O)NCCO)sc4Cl)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (example B.6) according to general procedure II. Light yellow solid. MS (ISP) 656.0 [(M−H)−]; mp 250° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([CH:31]3[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:34][CH2:35][CH2:36][OH:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:37][CH2:36][CH2:35][NH2:34])[N:18]=[C:17]([CH:31]3[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(C2CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: NCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C2CC2)nc1OCCN

Procedure:
According to the procedure described in Example 4b) 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide was reacted with 2-aminoethanol to give 1.28 g 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide. LC-MS: tR=4.04 min, [M−1]−=511.50.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.[C:13]1(S(OC)(=O)=O)C=CC=CC=1.[H-].[Na+].[OH-].[Na+].Cl>C(O)C.O.CN(C)C=O>[CH3:13][O:12][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1ccc(O)c(C(=O)O)c1
Reactant: COS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: COc1ccc(OC)c(C(=O)O)c1

Procedure:
A mixture of 7.05 g. (0.042 mole) of 5-methoxysalicyclic acid, 34.4 g. (0.2 mole) of methyl benzenesulfonate, 4.8 g. (0.2 mole) of sodium hydride and 100 ml. of N,N-dimethylformamide was heated at 125° C. for 16 hours, then poured into water. The mixture was extracted with diethyl ether and the extracts washed thrice with 200 ml. portions of 5N sodium hydroxide solution. The extracts were dried over magnesium sulfate, then evaporated to provide a residue which was dissolved in 100 ml. of ethanol and 100 ml. of 1N sodium hydroxide solution. The resulting solution was heated at reflux for 3 hours, then acidified with hydrochloric acid. The resulting solution was extracted with 200 ml. of diethyl ether. The extracts were washed with water, then dried. Evaporation provided 2,5-dimethoxybenzoic acid, m.p. 80°-85° C.
Reaction SMILES: FF.[CH3:3][O:4][C@@H:5]1[C@H:10]([O:11][CH3:12])[C@@H:9]([O:13][CH3:14])[C@H:8]([CH3:15])[O:7][C@H:6]1[O:16][N:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][N:31]=3)[N:26]=2)=[CH:21][CH:20]=1.[F:37][C:38]([F:45])([F:44])[C:39]([F:43])=[C:40]([F:42])[F:41].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[CH3:3][O:4][C@@H:5]1[C@H:10]([O:11][CH3:12])[C@@H:9]([O:13][CH3:14])[C@H:8]([CH3:15])[O:7][C@H:6]1[O:16][N:17]=[CH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:40]([F:42])([F:41])[CH:39]([F:43])[C:38]([F:45])([F:44])[F:37])=[CH:32][N:31]=3)[N:26]=2)=[CH:23][CH:24]=1
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON=Cc2ccc(-c3ncn(-c4ccc(O)cn4)n3)cc2)[C@@H]1OC
Agent: FF
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON=Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)C(F)(F)F)cn4)n3)cc2)[C@@H]1OC
Temperature: 25 °C
Yield: 24 %

Procedure:
Fluoroalkylation conditions were based on a paper by Timperley et al. J. Fluorine Chem. 2006, 127, 249. A solution of 4-[1-(5-hydroxy-pyridin-2-yl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde O-((2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-oxime in 10 mL anhydrous DMF/THF (1:1) under a N2 atmosphere was cooled at 0° C. while an excess of hexafluoropropylene gas was added over 15 min. Following addition, triethylamine (15 uL, 0.109 mmol) was added and the reaction mixture warmed to ambient temperature before concentration to dryness. Chromatography (EtOAc/hexanes, 1:1) afforded Compound 94 (16 mg, 24%). 1H NMR (CDCl3) δ 9.17 (s, 1H), 8.39 (d, J=7.68 Hz, 1H), 8.21 (d, J=8.22 Hz, 2H), 8.19 (s, 1H), 8.08 (d, J=7.68 Hz, 1H), 7.74 (d, J=8.22 Hz, 2H), 6.97 (s, 1H), 5.63 (d, J=1.85 Hz, 1H), 5.17 (m, 1H), 3.78 (dd, J=3.28, 1.99 Hz, 1H), 3.63 (m, 1H), 3.59 (s, 3H), 3.57 (s, 3H), 3.56 (s, 3H), 3.43 (dd, J=9.31, 3.36 Hz, 1H), 3.18 (t, J=9.48 Hz, 1H), 1.29 (d, J=6.26 Hz, 3H); EIMS 619 m/z (M+).