Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[O:28]=[C:29]1[NH:33][C@H:32]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[CH2:31][O:30]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:33]3[C@H:32]([CH2:34][OH:35])[CH2:31][O:30][C:29]3=[O:28])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
To a mixture of (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9, benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (442 mg), potassium carbonate (553 mg) and copper (I) iodide (76 mg) were added toluene (4 mL) and N,N′-dimethylethylenediamine (100 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol). To a solution of the obtained compound in dioxane (2 mL) and methanol (2 mL) was added 1 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was extracted with chloroform, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (344 mg).
Reaction SMILES: [CH3:1][S:2]([CH2:4][S:5][CH3:6])=[O:3].C([Li])CCC.CCCCCC.Br[CH2:19][CH:20]([CH2:39]Br)[O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.O>[C:35]([Si:22]([O:21][CH:20]1[CH2:39][C:4]([S:2]([CH3:1])=[O:3])([S:5][CH3:6])[CH2:19]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](OC(CBr)CBr)(c1ccccc1)c1ccccc1
Reactant: CSCS(C)=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSC1(S(C)=O)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of (methylsulfinyl)(methylthio)methane (27.70 g, 223.0 mmol) in tetrahydrofuran (90 mL) at −10° C. was added dropwise, a solution of 2.5 M n-butyllithium in hexane (89.2 mL, 223 mmol). The mixture was stirred at −10° C. for 2 hours. It was then cooled to −78° C. and transferred by cannula in a slow manner to a solution of [2-bromo-1-(bromomethyl)ethoxy](tert-butyl)diphenylsilane (42 g, 93 mmol, from Step 1) in tetrahydrofuran (70 mL, 900 mmol) held at −78° C. The mixture was stirred with warming to room temperature over 2 nights. Water was added, and then the product was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography (eluting with a gradient from 0-100% ethyl acetate/hexanes) afforded desired product as a mixture of diastereomers (34.1 g, 88%). 1H NMR (300 MHz, CDCl3), diastereomers: δ 7.74-7.58 (m, 8H), 7.48-7.31 (m, 10H), 4.52 (tt, 1H), 4.42 (tt, 1H), 3.05-1.99 (m, 8H), 2.47 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H), 1.05 (s, 9H), 1.02 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:15][CH2:16][CH3:17])=[C:4]([NH:9][C:10](=O)[CH2:11][C:12]#[N:13])[C:5]([Cl:8])=[N:6][CH:7]=1.BrC1C2N(CC)C(CC#N)=NC=2C(Cl)=NC=1.[N+:34]([O-])([O-])=[O:35].[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:3]2[N:15]([CH2:16][CH3:17])[C:10]([C:11](=[N:34][OH:35])[C:12]#[N:13])=[N:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CCNc1c(Br)cnc(Cl)c1NC(=O)CC#N
Agent: CCn1c(CC#N)nc2c(Cl)ncc(Br)c21
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1c(C(C#N)=NO)nc2c(Cl)ncc(Br)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 114.4 %

Procedure:
A solution of N-[5-bromo-2-chloro-4-(ethylamino)-3-pyridinyl]-2-cyanoacetamide III, (458 g, 1.45 mol) in glacial acetic acid (4.6 L) was heated to 100° C. After 3 h, LC/MS analysis indicated that the conversion to (7-bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)acetonitrile (IV) was completed. After allowing to cool to ambient temperature, the reaction was charged with sodium nitrate (230 g, 3.34 mol) in portions. Vigorous gas evolution and foaming was observed together with a ˜10° C. exotherm. After stirring at ambient temperature for 16 h, the solid was collected by filtration and dried to a constant weight to give 545 g of the desired product (V) as a light yellow solid. This was used in the next step without further purification. MS (ES+) m/z 328 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:30]>CC(O)C>[CH2:22]([O:21][C:20](=[O:29])[NH:19][CH2:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:30])[C:3]3=[C:10]([I:11])[N:9]=2)[CH2:13][CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(NC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1)OCc1ccccc1
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 110 °C

Procedure:
A solution of benzyl {[trans-4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate (1.70 g, 0.00324 mol) in IPA (30 mL) was cooled to −78° C., treated with a stream of ammonia gas over 3 min. and then heated at 110° C. in a Parr vessel overnight. The reaction solution was concentrated in vacuo and residue washed with water to afford 1.37 g of desired product. 1H NMR (400 MHz, CDCl3): δ=1.08-1.17 (m, 2H), 1.88 (m, 1H), 1.71-1.81 (m, 2H), 1.91-1.94 (m, 2.00-2.04 (m, 2H), 2.90 (m, 1H), 3.13 (t, J=6.4 Hz, 2H), 4.86 (br, 1H), 5.11 (s, 2H), 5.76 (br, 2H), 7.00 (d, J=5.2 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 7.31-7.37 (m, 5H). MS (ES+): m/z 5.7.36 [MH+].
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=2[Cl:21])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[Cl-].[NH4+].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[NH:32][N:31]=[N:30][N:20]=3)=[CH:15][C:14]=2[Cl:21])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C#N)cc2Cl)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(-c3nnn[nH]3)cc2Cl)ccc(C(C)=O)c1O
Temperature: 120 °C
Yield: 76.4 %

Procedure:
A mixture of 1-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-3-(2-chloro-4-cyanophenoxy)propane (776 mg), ammonium chloride (700 mg), sodium azide (700 mg) and dimethylformamide (2 ml) was heated at 120° C. for 1 hour. After the inorganic salt was filtered off, the filtrate was concentrated under reduced pressure. The residue was acidified with 1N-HCl and the resultant precipitate was recovered by filtration. Recrystallized from methanol gave 659 mg of 1-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-3-[2-chloro-4-(tetrazol-5-yl)phenoxy]propane as white microcrystals. m.p. 214°-216° C.
Reaction SMILES: C12CC3CC(CC(C3)[CH:2]1[NH:11][C:12]([C:14]13[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])([CH2:18][CH2:19]1)[CH2:16][CH2:15]3)=[O:13])C2.C12CC3CC(CC(C3)C1N)C2.CN(C=O)C.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:27]([S:24]([CH2:23][CH2:22][C:17]12[CH2:18][CH2:19][C:14]([C:12]([NH:11][CH3:2])=[O:13])([CH2:21][CH2:20]1)[CH2:15][CH2:16]2)(=[O:26])=[O:25])[CH3:28]
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)NC3C4CC5CC(C4)CC3C5)(CC1)CC2
Agent: NC1C2CC3CC(C2)CC1C3
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)CCC12CCC(C(=O)NC)(CC1)CC2
Reaction time: 8 h

Procedure:
Amide 1-6 was made from acid chloride 1-5 (810 mg, 2.96 mmol) as one member of a 96 compound library, employing the technique of parallel synthesis using the Myriad Core System/nMiniblock. According to the general procedure, 0.10 mmol of each amine (2-adamantylamine for this product) was weighed into the miniblock reaction tubes, and 0.350 ml of dry DMF and 0.55 ml of dry diisopropylethylamine was added to each tube. A 0.25 M solution of the acid chloride in dry acetonitrile was prepared, and 0.400 ml of this solution was dispensed to each tube and the reactions were incubated and stirred overnight under an inert nitrogen atmosphere. The products were purified using a Fraction Lynx HPLC (with detection according to mass spectrum) equipped with a Waters Xterra MS C18 5 um 19×50 nm reverse phase column running a gradient of water/acetonitrile (0.1% TFA). The fractions containing product were concentrated to remove some of the acetonitrile and the lyophilized to provide pure product 4-[2-(ethylsulfonyl)ethyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide 1-6 as a white fluffy amorphous solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][CH2:19]OC)(=[O:17])[CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCC>[CH2:1]([O:8][CH2:9][CH:10]([O:13][CH2:19][O:18][C:14](=[O:17])[CH2:15][CH3:16])[CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCl)COCc1ccccc1
Reactant: CCC(=O)OCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Product: CCC(=O)OCOC(CCl)COCc1ccccc1

Procedure:
204.0 g of 3-benzyloxy-1-chloro-2-propanol, 660 ml of hexane, 626.3 g of methoxymethyl propionate and 5.79 g of p-toluenesulfonic acid mono-hydrate were placed into a 2-liter 3-neck round bottom flask equipped with a thermometer, mechanical stirrer, nitrogen inlet and an efficient distillation column. The reaction mixture was heated to reflux. The distillate was taken off at about 10:1 to 15:1 reflux ratio keeping the head temperature below 60° C. Samples were taken to monitor the progress of the reaction. The reaction was quenched when the desired level of methyl acetal was reached which is usually less than about 4% methyl acetal. The quench was carried out by rapidly adding a solution of 11.55 g of sodium carbonate in 310 ml of water directly to the hot reaction mixture. The aqueous layer was washed with additional water and/or base to remove any residual propionic acid. The volatiles were removed to leave the crude product as a mobile liquid. Yield: 285.2 g, (97.8%); 92.6% pure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:22][C@@H:23]([CH3:29])[C:24]([NH:26][CH2:27][CH3:28])=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:22][C@@H:23]([CH3:29])[C:24]([NH:26][CH2:27][CH3:28])=[O:25]
Reactant: CCNC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Product: CCNC(=O)[C@H](C)NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
Following the general procedure of EXAMPLEs 4 and 14–164 and making non-critical variations and reacting tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3) with (2S)-2-amino-N-ethylpropanamide (VI), the title compound is obtained.
Reaction SMILES: C([O:5]C(N(C1C=CC=CC=1)[C@H](CO)C)=O)(C)(C)C.[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.BrN1C(=O)CCC1=O.CO>CN(C=O)C>[C:32]1([P:25](=[O:5])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C[C@@H](CO)N(C(=O)OC(C)(C)C)c1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CO
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of the N-tert-butoxycarbonyl phenyl alaninol (1.42 mmol) and triphenylphosphine (2 equiv) in DMF, N-bromosuccinimide (2 equiv) was slowly added. The reaction was warmed to 50° for 15 min and then cooled to 20°. Methanol (0.5 mL) was added to destroy the excess reagent. After 5 min, ether was added, and the ether layer was washed with water, saturated sodium carbonate, and saturated NaCl and then evaporated to a solid under high vacuum. The product was extracted twice into hexane, leaving a residue of triphenylphosphine oxide. After evaporation of the solvent, the residue was again triturated with hexane to afford the 1-Bromo-2-(tert-butoxycarbonyl)amino-3-phenyl propane:
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:35](=[O:37])[CH3:36])[CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH:16]([CH3:34])[CH2:15]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C(N([C@H]1C2C(=CC=CC=2)N(C(=O)C2C=CC(OC)=CC=2)[C@@H](C)C1)C1C=CC(OCC(O)=O)=CC=1)(=O)C.COC(=O)COC1C=CC(Br)=CC=1>>[C:35]([N:13]([C@H:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C@@H:16]([CH3:34])[CH2:15]1)[C:10]1[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:38])=[O:2])=[CH:8][CH:9]=1)(=[O:37])[CH3:36]
Reactant: COC(=O)C(C)(C)c1ccc(N(C(C)=O)C2CC(C)N(C(=O)c3ccc(OC)cc3)c3ccccc32)cc1
Agent: COC(=O)COc1ccc(Br)cc1
Agent: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(OCC(=O)O)cc3)C[C@@H]2C)cc1
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(C(C)(C)C(=O)O)cc3)C[C@@H]2C)cc1

Procedure:
(2S,4R)-2-(4-{Acetyl-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-amino}-phenyl)-2-methyl-propionic acid was prepared via saponification of 2-(4-{acetyl-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]amino}-phenyl)-2-methyl-propionic acid methyl ester, as described in the synthesis of (2S,4R)-(4-{acetyl-[1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-amino}-phenoxy)-acetic acid. The methyl ester was prepared following general procedure D, substituting 2-(4-bromo-phenyl)-2-methyl-propionic acid for methyl-2-(4-bromophenoxy)-acetate.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:25][CH2:24][C:18]3[N:19]=[CH:20][N:21]=[C:22](O)[C:17]=3[CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13].CN(C)C1C=CC=CC=1.[OH-].[K+]>C(#N)C.C1(OC)C=CC=CC=1.C(Cl)(Cl)Cl.CN(C)C=O>[Br:3][C:22]1[C:17]2[CH2:16][N:15]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:14][C:11]=3[C:12]#[N:13])[CH2:25][CH2:24][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: O=P(Br)(Br)Br
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(O)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: COc1ccccc1
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Br)c2C1
Temperature: 0 °C
Yield: 35.8 %

Procedure:
POBr3 (1.61 g, 5.6 mmol) was added portionwise over 2 min to a mixture of 5-chloro-2-(4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (0.82 g, 2.8 mmol), N,N-dimethylaniline (0.7 mL), and N,N-dimethylformamide (0.02 mL) in acetonitrile (10 mL) and anisole (10 mL). The mixture was heated under reflux for 2.5 h and LC-MS showed reaction was complete. After cooling the mixture was diluted with chloroform (20 mL) and poured into a stirred mixture of ice (50 g), 50% KOH (8 mL) and chloroform (100 mL). The organic layer was separated and the aqueous layer was extracted with chloroform (25 mL×2). The combined organic layers were washed with brine (100 mL), dred (Na2SO4), filtered and concentrated. The residue was purified by silica gel column to yield a brown solid (0.35 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[NH:7][C:8](=[O:14])/[CH:9]=[C:10](\[O:12][CH3:13])/[CH3:11])([O-])=O.C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[NH:7][C:8](=[O:14])/[CH:9]=[C:10](\[O:12][CH3:13])/[CH3:11]
Reactant: CO/C(C)=C\C(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CO/C(C)=C\C(=O)Nc1cccc(N)c1
Temperature: 27 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
48 g of powdered iron were added over 15 minutes at 20° C. to a mixture of 18.9 g of m-nitro-3-methoxy-crotonanilide, 64 ml of 95% ethanol, 16 ml of water and 0.8 ml of 22° Be hydrochloric acid and the mixture was stirred for 11/2 hours at 27° C. The interior temperature was raised to 60° C. and the temperature was slowly lowered to 25° C. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 13.6 g of m-amino-3-methoxy-crotonanilide. The product melted at 132° C. and after crystallization from ethanol still melted at 132° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13]
Reactant: CCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
A mixture of 2.15 g of 6,7-dichloro-2-ethyl-5-methoxybenzo[b]thiophene and 15 g of pyridine hydrochloride is stirred at 170°-180° for 90 min. The mixture is cooled, triturated with water and extracted three times with dichloromethane. The combined organic extracts are washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to an oily residue. Purification by column chromatography (silica gel-etherpentane 50:50) affords 1.5 g of 6,7-dichloro-2-ethyl-5-hydroxybenzo[b]thiophene as off-white crystals, mp 69°-70°.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[C:11]([N+:23]([O-])=O)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.OC1C=CC(SC2C=CC(NC(=O)C3C=CC=C(C(F)(F)F)C=3)=CC=2[N+]([O-])=O)=CC=1>>[NH2:23][C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][C:12]=1[S:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Agent: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Product: Nc1cc(NC(=O)c2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Yield: 80 %

Procedure:
The title compound was prepared according to the procedure of Example 114C substituting the product from Example 116B for the product from Example 114B to provide the title compound (0.5 g, 80%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1
Reactant: c1nc[nH]n1
Product: Clc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-chloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14](=[O:16])[CH3:15])[CH2:10][C@H:9]1[CH2:17][N:18](C(OCC1C=CC=CC=1)=O)[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[F:27])=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+]>Br.C(O)(=O)C.CCOCC>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14](=[O:16])[CH3:15])[CH2:10][C@H:9]1[CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[F:27])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1C[C@H](SC(C)=O)C[C@H]1CN(Cc1cc(F)ccc1F)C(=O)OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCOC(=O)N1C[C@H](SC(C)=O)C[C@H]1CNCc1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
50 mg (0.09 mmol) (2S,4R)-4-acetylsulfanyl-2-{[benzyloxycarbonyl-(2,5-difluoro-benzyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid butyl ester were dissolved in 130 μl 33%HBr in acetic acid and stirred at 0° C. for 30 min, and at RT for 1 h. The solution was diluted with ether and poured on saturated NaHCO3 solution, carefully. The inorganic layer was extracted with EtOAc, the combined organic phases were washed with water and brine, dried over Na2SO4 and evaporated. Column chromatography yielded 13 mg (35%) (2S,4R)-4-acetylsulfanyl-2-[(2,5-difluoro-benzylamino)-methyl]-pyrrolidine-1-carboxylic acid butyl ester as colorless oil, MS: 401 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([C:14]([OH:16])=O)=[C:12]([F:17])[C:11]([O:18][CH3:19])=[CH:10][CH:9]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O.O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:14]([C:13]2[C:8]([Cl:7])=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[F:17])=[O:16])=[CH:26][CH:25]=1)[CH3:32]
Reactant: COc1ccc(Cl)c(C(=O)O)c1F
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)c2c(Cl)ccc(OC)c2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
Oxalyl chloride (193 μl, 2.21 mmol) was added dropwise to a solution of 6-chloro-2-fluoro-3-(methyloxy)benzoic acid (300 mg, 1.47 mmol) in dichloromethane (5 ml). To this was added dimethylformamide (1 drop) and the reaction was stirred at room temperature for 3 hrs. The solvent was evaporated to afford a yellow semi-solid. This semi-solid was dissolved in dichloromethane (5 ml) and ethyl (4-aminophenyl)acetate (316 mg, 1.76 mmol) followed by triethylamine (287 μl, 2.06 mmol) were added. The resultant solution was stirred at room temperature overnight. The reaction was diluted with water and the phases separated. The organic layer was dried (Na2SO4), the solvent evaporated and the residue purified by flash chromatography (Biotage SP4, 25+M silica column, 0→50% ethyl acetate/petrol) to afford the title as a yellow semi-solid (506 mg, 94%). MS (ES+) m/z 366 [M+H+] (C18H1735ClFNO4).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]#[N:26]>CN(C=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][C:25]#[N:26])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(OCC#N)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A slurry of 357 mg (1.6 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and 650 mg (4.7 mmol) of K2CO3 in 5 ml DMF was cooled to 0° C. and treated with 220 μl (3.2 mmol) of bromoacetonitrile dropwise. The brown slurry was warmed to room temperature, stirred for 1.5 h, then was quenched with water (20 ml) and was extracted with benzene (3×). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (hexanes:EtOAc, 17:3) to give the title compound. 1H-NMR (CDCl3) δ 1.34 (s, 12 H), 4.79 (s, 2 H), 6.96 (d, J=8.5 Hz, 2 H), 7.80 (d, J=8.5 Hz, 2 H). Mass Spectrum (ESI) m/e=260.2 (M+1, triplet).