Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(O)(=O)C>[C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[S:21]([O:3][C@@H:2]1[C@@H:4]([OH:5])[C@@H:6]([CH2:8][OH:9])[O:7][C@H:1]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][CH:13]=[N:14][C:15]=2[NH2:19])([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H](O)[C@H]1O
Solvent: CC(=O)O
Product: CS(=O)(=O)O[C@@H]1[C@@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
9-β-D-Arabinofuranosyl adenine (ara-A) is synthesized when the 3',5'-di-O-isopropylidene derivative of 9-(β-D-xylofuranosyl)adenine is treated with methanesulphonyl chloride to convert it to the corresponding 2'-O-mesyl derivative, which is cleaved by acetic acid to produce 9-(2'-O-mesyl-β-D-xylofuranosyl)adenine, which is treated with sodium methoxide in methanol to produce the 2',3'-epoxide, which is treated with sodium in aqueous dimethylformamide to open the ring and produce ara-A which is purified by crystallization.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH3:8]>O>[C:1]1(=[O:7])[NH:8][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:1]=[CH:2][C:3]1[CH:4]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: N
Reactant: O=C1C=CC(=O)O1
Solvent: O
Product: C=Cc1ccccc1
Product: O=C1C=CC(=O)N1

Procedure:
To a 1 liter double walled, oil heated autoclave, having an anchor stirrer 225 g of SMA and 334.4 g of water were added. The SMA had a maleic anhydride content of 26 mole % and a molecular weight of 80.000 g/mole. To this reaction mixture was added 150 g of palm oil (from Cargill, USA) and 40.6 g of a 25% NH3 solution so that the maleic anhydride (MA):NH3 ratio was about 1:1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:12])([CH3:11])[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][I:22])(=[O:15])[CH3:14].CCOCC>ClC1C=CC=CC=1Cl>[I-:22].[CH3:1][C:2]1[C:3]([CH3:12])([CH3:11])[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:13]([CH3:14])=[O:15]
Reactant: CC(=O)OCCCCCI
Reactant: CC1=Nc2ccccc2C1(C)C
Solvent: CCOCC
Solvent: Clc1ccccc1Cl
Product: CC(=O)OCCCCC[N+]1=C(C)C(C)(C)c2ccccc21
Product: [I-]
Temperature: 120 °C

Procedure:
A mixture of 2,3,3-trimethyl-3H-benzo[b]azole (2.39 g, 15 mmol) and 5-iodopentyl acetate (3.84 g, 15 mmol) in 1,2-dichlorobenzene (15 ml) were heated at 120° C. for 6 h and then cooled to ambient temperature. The mixture was then dripped into Et2O which precipitated the title compound as a red gum which was collected and used without any further purification in subsequent reactions.
Reaction SMILES: Cl.O.[N+:3]([C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-])=O>C(O)C>[NH2:3][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=Cc1ccccc1N
Yield: 84.1 %

Procedure:
A mixture of 2.2 g of reduced iron, 0.5 ml of conc. hydrochloric acid and 2.5 ml of water was added to a solution of 2.2 g of ethyl o-nitrocinnamate in 30 ml of ethanol. After heating under reflux for 1 hour, insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. An aqueous sodium hydrogen carbonate solution was added to the residue followed by extraction with toluene. After the extract was washed with water and dried, the solvent was distilled off to obtain 1.6 g of ethyl o-aminocinnamate as yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.FC(F)(F)C(O)=O.[F:26][C:27]([F:42])([F:41])[C:28]([N:30]1[CH2:35][C:34]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:33][CH2:32][CH2:31]1)=[O:29]>C(#N)C>[F:42][C:27]([F:26])([F:41])[C:28]([N:30]1[CH2:35][C:34]2([CH2:40][CH2:39][N:38]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][OH:11])[CH:4]=3)[CH2:37][CH2:36]2)[O:33][CH2:32][CH2:31]1)=[O:29]
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Reactant: OCCc1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(N1CCOC2(CCN(Cc3cccc(CCO)c3)CC2)C1)C(F)(F)F
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 2-(3-(bromomethyl)phenyl)ethanol (example 6, step a) (0.223 g) dissolved in acetonitrile (1 mL) was added dropwise to a stirred solution of triethylamine (0.318 mL) and 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (0.38 g) in acetonitrile (2 mL) at 20° C., over a period of 2 minutes. The resulting mixture was stirred at 20° C. for 3 hours. The solvent was evaporated off and residue partitioned between dichloromethane and water, the aqueous layer was re-extracted twice with DCM and the combined organics were dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 6% methanol and 1% triethylamine in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.260 g.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[C:43](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:43][N:3]1[NH:2][N:1]=[C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:10][CH:11]=2)[NH:4]1
Reactant: O=C([O-])O
Reactant: Cc1c(Cl)cccc1C1C(C(=O)Nc2ccc(-c3nnn[nH]3)cc2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cc1c(Cl)cccc1C1C(C(=O)Nc2ccc(C3=NNN(C)N3)cc2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.2 %

Procedure:
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide (32 mg, 0.0524 mmol) in acetone (5 mL), sodium bicarbonate (45 mg, 0.6 mmol) and dimethyl sulfate (0.11 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (18 mg) and the other regioisomer (3 mg).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:18]Br>C(O)(=O)C.O>[Br:18][C:9]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:8]=1[NH2:10]
Reactant: BrBr
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1-n1nc(C(C)(C)C)c(Br)c1N
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
To a solution of 3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (1.00 g, 4.36 mmol) in acetic acid (10 mL) was added bromine (662 mg, 0.21 mL, 4.14 mmol) dropwise. The reaction mixture was stirred for 5 min, and then diluted with water (50 mL), causing a solid to precipitate. The solid was collected by filtration, then dissolved in EtOAc (50 mL). The EtOAc solution was then washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated under reduced pressure to afford the product (935 mg, 70%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 1.32 (s, 9H), 2.04 (s, 3H) 5.02 (s, 2H), 7.20-7.38 (m, 4H). ES-MS m/z 308.6 (MH+); HPLC RT (min) 3.15.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[F:7][C:8]1[CH:22]=[CH:21][C:11]2[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][O:14][C:10]=2[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:17][CH2:16][CH:15]([C:12]2[C:11]3[CH:21]=[CH:22][C:8]([F:7])=[CH:9][C:10]=3[O:14][N:13]=2)[CH2:20][CH2:19]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(C3CCN(CCCCCl)CC3)noc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
1-bromo-4-chlorobutane (9.4 g, 60 mmol) is dissolved in 50 ml of DMF, and thereto 4-(6-fluoro-1,2-benzisoxazolyl)-piperidine (4.4 g, 20 mmol) and anhydrous potassium carbonate powder (8.2 g, 60 mmol) is added. The mixture is stirred at room temperature for 48 hours and the reaction is terminated. To the reaction solution is added 100 ml of water and 100 ml of ethyl acetate. The mixture is shaked and the aqueous layer is further extracted with 100 ml of ethyl acetate. The ethyl acetate layers are combined, backwashed with 200 ml of water, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to 50 ml volume and extracted with 5% HCl (30 ml×3). The extracting solution is combined, adjusted to pH 7 with 5% NaOH, and further extracted with ethyl acetate (30 ml×3). The extracting solution is combined, dried and evaporated to dryness to obtain 1.8 g of 3-(1-(4-chlorobutyl)-4-piperidinyl)-6-fluoro-benzisoxazole, with a yield of 30%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[Se](=O)=[O:13]>O1CCOCC1>[O:11]=[C:10]1[C:5]2[C:6](=[N:7][C:2]([CH:1]=[O:13])=[CH:3][CH:4]=2)[CH2:8][O:9]1
Reactant: O=[Se]=O
Reactant: Cc1ccc2c(n1)COC2=O
Solvent: C1COCCO1
Product: O=Cc1ccc2c(n1)COC2=O
Temperature: 100 °C
Yield: 79.7 %

Procedure:
A solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (1.41 g, 9.46 mmol) in dioxane (50 mL) is treated with selenium dioxide (1.2 g, 10.8 mmol) and the reaction mixture is heated at 100° C. for 3 h. Additional selenium dioxide (1.2 g, 10.8 mmol) is added at 3 and 6 hours and the reaction mixture is heated at 100° C. The reaction is heated at 100° C. for an additional 42 h. The reaction mixture is filtered through celite and washed with dioxane. The filtrate is concentrated under reduced pressure and subject to chromatography (silica gel, EtOAc/hexane). The high Rf product containing fractions are concentrated to give 5-Oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (1.23 g, 80%). The low Rf containing fractions are concentrated to give 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carboxylic acid (159 mg, 9%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][C@@H:13]([CH3:17])[CH2:12]2)=[N:7][CH:6]=1)[CH3:2].[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](Cl)=[N:22][N:21]=1.C(N(CC)CC)C>CN1C(=O)CCC1.O>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]([Cl:19])=[N:21][N:22]=3)[C@@H:13]([CH3:17])[CH2:12]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: CCOC(=O)c1ccc(N2CCN[C@@H](C)C2)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(N2CCN(c3nnc(Cl)c4ccccc34)[C@@H](C)C2)nc1
Yield: 30.3 %

Procedure:
A solution of 6-((S)-3-methyl-piperazin-1-yl)-nicotinic acid ethyl ester (1.0 g, 4.0 mmol, 1 eq), 1,4-dichlorophthalazine (840 mg, 4.2 mmol, 1.05 eq) and triethyl amine (3.9 g, 2.8 mL, 38 mmol, 9.5 eq) in NMP (8 mL) is heated at 100 C for 26 h. Reaction is diluted with water (15 mL) and extracted with EtOAc (3×25 mL). The combined organic fractions are dried over magnesium sulfate, concentrated and purified by silica gel chromatography (5-50% EtOAc/Heptane) to yield the desired compound (500 mg, 30% yield).
Reaction SMILES: [Na+].[CH3:2][S:3]([CH2-:5])=[O:4].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2C(=O)O[C:17](=[O:18])[C:16]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:15]23)=[CH:10][CH:9]=1.Cl.C(Cl)Cl>CS(C)=O>[CH3:2][S:3]([CH2:5][C:17]([C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[NH:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)=[O:18])=[O:4]
Reactant: [CH2-]S(C)=O
Reactant: COc1ccc(-n2c(=O)oc(=O)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(Nc2ccccc2C(=O)CS(C)=O)cc1
Reaction time: 1 h

Procedure:
To a 2 molar solution of dimsyl sodium in dimethylsulfoxide (365 ml.), cooled to 10° C., was added a solution of 65 g. of N-(4-methoxyphenyl)isatoic anhydride in 150 ml. dimethylsulfoxide with stirring and stirring was continued 30 minutes at room temperature and 1 hour at 50° C. The reaction mixture was poured onto 1200 g. of ice, 70 ml. of concentrated hydrochloric acid was added, and the mixture was extrated with methylene dichloride. The extract was washed with water, dried (MgSO4), and concentrated under reduced pressure to give, after recrystallization from benzenecyclohexane 45 g. 2-(methylsulfinyl)-2'-(4-methoxyanilino)acetophenone; m.p. 115°-116° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17](Cl)=[O:18].Cl.[C:21]1([C:27]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:46]1([C:27]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH:34]3[C:17](=[O:18])[CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH3:8])[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: COc1ccccc1CC(=O)Cl
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)C1NCC2C1C(c1ccccc1)(c1ccccc1)CC(O)C2(O)c1ccccc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
4.2 cm3 of triethylamine and then 2.4 g of (2-methoxyphenyl)acetic acid chloride in 50 cm3 of dichloromethane are added to a solution of 4.5 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindole-4,5-diol hydrochloride in 100 cm3 of dichloromethane, cooled to 0° C. The reaction mixture is stirred at room temperature for 90 minutes; it is washed with twice 10 cm3 of water, and is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid which has crystallized is taken up in. 100 cm3 of diisopropyl ether and then filtered off and washed with 50 cm3 of a saturated solution of sodium bicarbonate and then 50 cm3 of diisopropyl ether. 4.35 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-(2-methoxyphenyl)- acetylperhydroisoindole-4,5-diol are obtained in the form of a light beige solid which melts at 278° C.
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].O>C1COCC1.CC(OC)(C)C>[CH2:3]([O:10][CH2:12][C:13]([OH:15])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)CCl
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C(O)COCc1ccccc1
Temperature: 50 °C
Yield: 70.4 %

Procedure:
To a suspension of KOH (17.84 g, 118 mmol) in THF (200 mL) was added benzyl alcohol (42 mL, 424 mmol). After 1.5 h the mixture was heated to 50° C. for 1.5 h and cooled to rt afterwards. Chloroacetic acid (10 g, 106 mmol) was added and the mixture was heated to 80° C. After 1.5 h the mixture was cooled to rt and water and MTBE was added. The layers were separated, the aqueous layer was extracted with MTBE, the pH of the aqueous layer was adjusted to pH=2 with 6N HCl and extracted with MTBE. The extracts of the acidic layer were dried and the solvent removed under reduced pressure to give 12.4 g of the crude product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[C:18]([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][C:31]=1[O:38][CH3:39].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:37])[CH3:18])=[CH:32][C:31]=4[O:38][CH3:39])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(C=O)ccc1OCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 75 °C
Yield: 87.4 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 mol), K2CO3 (5.2 g, 0.04 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]methanone (6.6 g, 22 mmol), and dimethylformamide (60 ml) was heated at 75° C. for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent was concentrated to yield initially an oil, which solidified upon standing. The solid was triturated with hexane and collected to afford 7.7 g of the product as a waxy solid. The compound was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with dichloromethane/methanol (5%). Concentration of the appropriate fractions yielded 5.1 g of off-white solid 1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone, which when recrystallized from ethyl alcohol yielded 3.2 g (36%) of feathery-white needles, m.p.=88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][S:12](O)(=[O:14])=[O:13]>S(=O)(=O)(O)N.O>[N+:8]([C:3]1[CH:4]=[C:5]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:6]=[CH:7][C:2]=1[Cl:1])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: O=S(=O)(O)Cl
Agent: NS(=O)(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 100 °C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
157.6 g (1.0 mol) of 2-chloronitrobenzene are added to 699 g (6.0 mol) of chlorosulfonic acid and 2 g of sulfamic acid such that the temperature does not exceed 40° C. After addition is complete, the mixture is heated to 100° C. and stirred at this temperature for 6 hours. The reaction mixture is dripped into water at 15° C., and the precipitated crystals are filtered off with suction and washed with water. 236.2 g of 2-nitrochlorobenzene-4-sulfonyl chloride having a water content of 1.5%, corresponding to 232.7 g of 2-nitrochlorobenzene-4-sulfonyl chloride (90.8% of theory), are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:26][CH:25]=1)=[O:23]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([O:19][CH2:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH:31]([F:32])[F:33])=[CH:28][CH:29]=2)=[O:23])=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)COC1
Product: O=C(CC1(NC(=O)OCc2ccccc2)COC1)OCC(=O)c1ccc(OC(F)F)cc1

Procedure:
Prepared by Method E using (3-{[(benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acid (Preparation 25, 0.3 g, 1.13 mmol) and 2-bromo-1-[4-(difluoromethoxy)phenyl]ethanone (0.315 g, 1.19 mmol) to afford the title compound.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15]([OH:17])=[O:16].[C:24](O)([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1>[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15]([O:17][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:16]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)O
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Benzenesulfonyl chloride (12.8 mL, 100 mmol) was added rapidly to a solution of 3-methyl-4-nitrobenzoic acid (9.06 g, 50 mmol) in dry pyridine (25 mL) at 40° C. The reaction was mildly exothermic. The cloudy, orange solution was stirred for 5 min, then t-butanol (4.7 mL, 50 mmol, 1 eq.) was added. After 1 h, the reddish-orange mixture was poured into ice/water (200 mL), and the resulting mixture was stirred briskly for 1 h. The solid was collected by suction filtration, washed with H2O, and dissolved in toluene (200 mL). The solution was dried (MgSO4) and filtered through a pad of silica gel eluting with toluene. Concentration gave the title compound as a yellow oil which crystallized under vacuum (9.67 g, 82%).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].C(N(C(C)C)CC)(C)C.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH2:40][NH2:41])[CH:37]=[CH:38][CH:39]=1>ClCCl>[O:1]=[C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([NH:41][CH2:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:42])[F:43])[CH:35]=1)=[O:21]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.051 g, 0.173 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.072 g, 0.190 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.045 mL, 0.259 mmol) followed by (3-(trifluoromethyl)phenyl)methanamine (0.030 mL, 0.207 mmol). After stirring overnight, the reaction was loaded onto a silica gel column (SF15-12, Analogix®, Burlington, Wis.), and the title compound was eluted with a gradient of 0.4% to 4.5% methanol/dichloromethane over 20 minutes with a flow rate of 30 mL/minute. 1H NMR (300 MHz, CDCl3) δ ppm 7.50-7.55 (m, 1H), 7.37-7.44 (m, 2H), 7.17-7.34 (m, 11H), 6.30 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H), 4.07 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 2.81 (t, J=6.5 Hz, 2H); MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([O:45]C)=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:63][N:64]([CH3:69])[CH2:65][CH2:66][CH2:67][NH2:68]>CN(C=O)C>[CH3:63][N:64]([CH3:69])[CH2:65][CH2:66][CH2:67][NH:68][C:43]([C:40]1[S:39][C:35]2[N:36]=[CH:37][N:38]=[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[O:47][CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[C:34]=2[C:41]=1[CH3:42])=[O:45]
Reactant: CN(C)CCCN
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 3-Dimethylamino-1-propylamine (69 μL, 0.625 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was recrystallised from DMSO to yield off-white solid (0.031 g, 51%).