Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=CC=1>CCOC(C)=O.O>[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([C:11]2[CH:12]=[CH:13][C:14]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)=[CH:15][CH:16]=2)[CH2:34][CH2:35]1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CN1CCC(c2ccc(Br)cc2)CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 4-(4-bromophenyl)-1-methylpiperidine (236 mg, 0.93 mmol). The reaction was then allowed to cool to rt and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give a viscous brown solid (236 mg, used without further purification). 1H NMR (400 MHz, MeOD) δ 7.70 (d, J=7.5 Hz, 2H), 7.25 (d, J=7.5 Jz, 2H), 3.26-3.23 (m, 2H), 2.69-2.64 (m, 1H), 2.60-2.54 (m, 5H), 1.92-1.91 (m, 4H), 1.33 (s, 12H); MS ESI 302.2 [M+Na]+, calcd for [C18H28BNO2+Na]+ 302.22.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][CH2:38][C:39]([NH2:41])=[O:40]>>[NH2:41][C:39](=[O:40])[CH2:38][CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:21]2[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: NCCC(N)=O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NCCC(N)=O)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 3-aminopropionamide, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=437.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C([O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[N:18][CH:17]=1)C.Cl>C1COCC1.C(OCC)(=O)C.O>[Br:22][C:19]1[N:18]=[CH:17][C:16]([C:15]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(Br)nc1
Reactant: O=C1CCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)nc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 71 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.38 g, 10 mmol) in 30 mL of THF was treated with NaH (60 percent, 0.6 g, 15 mmol). After the addition of 6-Bromo-nicotinic acid ethyl ester (2.3 g, 10 mmol), the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(6-Bromo-pyridine-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.28 g, 7.1 mmol) as red solid in 71% yield.
Reaction SMILES: [O-]CC.[Na+].[CH:5]1([C:11](=[O:13])[CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(O)C.CCOCC>[CH:5]1([C:11](=[O:13])[CH:12]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC(=O)C1CCCCC1
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)C1CCCCC1
Yield: 69.6 %

Procedure:
A sodium ethoxide solution (21% by weight in ethanol, 6.805 gm, 21 mmol) was added to a mixture of 1-cyclohexyl-1-ethanone (18.749 g, 140 mmol, from Aldrich) and 4-fluorobenzaldehyde (17.37 g, 140 mmol, from Aldrich) in ethanol (100 ml), stirring under argon. The solution was allowed to stir 1.5 hours. The reaction mixture was then concentrated to afford an orange oil. The oil was dissolved in ether, washed with saturated NH4Cl and brine, then dried over Na2SO4, filtered and concentrated to an orange oil. The oil was purified by distillation (bp=143° C. at 1.3 mm Hg). The resultant yellowish oil slowly solidified to afford the title compound as hard yellow crystals (22.640 gm, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#Cc1ccc(Br)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in conc. H2SO4 (10 mL) was added dropwise at 0° C. nitric acid (6 mL). The reaction mixture was stirred at 0° C. for 30 min, and then at room temperature for 2.5 h. The resulting solution was poured into ice-water. The white precipitate was collected via filtration and washed with water until the washings were neutral. The solid was recrystallized from an ethanol/water mixture (1:1, 20 mL) twice to afford 4-bromo-3-nitrobenzonitrile as a white crystalline solid (2.8 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 150.4, 137.4, 136.6, 129.6, 119.6, 117.0, 112.6; HPLC ret. time 1.96 min, 10-100% CH3CN, 5 min gradient; ESI-MS 227.1 m/z (MH+).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([O:42][CH3:43])[CH:36]=1.CN(C)C=O>C(OC)(C)(C)C.O>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][CH2:13][C:4]2=[O:3])=[CH:36][C:37]=1[O:42][CH3:43]
Reactant: C[Si](C)(C)OC1=Cc2ccccc2CC1
Reactant: COc1cc(Br)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COc1cc(C2C(=O)CCc3ccccc32)ccc1Cl
Temperature: 90 °C

Procedure:
Charge an oven dried, argon flushed 25-mL 2-necked round bottomed flask equipped with a stirring bar and reflux condenser with 2-trimethylsilyloxy-3,4-dihydronaphthalene (0.4247 grams, 1.9449 mmoles) and tetra-n-butylammonium fluoride (2.3 mL, 2.30 mmoles, 1 M in tetrahydrofuran), stir for a few minutes and then add 4-bromo-2-methoxy-1-chlorobenzene (0.4336 grams, 1.9577 mmoles) dichlorobis(tri-ο-tolyl-phosphine)palladium (0.0154 grams, 0.0196 mmoles) and 5 mL dimethylformamide. Heat the reaction mixture for 18 hours (oil bath temperature about 90° C.), cool to RT and add 5 mL water and 10 mL t-butylmethyl ether. Separate the layers, extract the aqueous layers with 3×5 mL t-butylmethyl ether, wash the combined organic layers with water and saturated salt solution, dry over magnesium sulfate and concentrate using a Buchi rotavapor to yield the final product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]1([N:15]=[C:16]=S)[CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[CH:12]1([NH:15][C:16]2[NH:10][C:4]3[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=3[N:11]=2)[CH2:14][CH2:13]1
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1N
Reactant: S=C=NC1CC1
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: Clc1cc2[nH]c(NC3CC3)nc2c(Cl)c1Cl
Yield: 83.3 %

Procedure:
3,4,5-Trichloro-1,2-phenylenediamine (3.02 g, 14.28 mmol), cyclopropyl isothiocyanate (1.53 g, 15.42 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (8.24 g, 19.45 mmol) and pyridine (55 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 3.29 g (83%) of a white solid. MS (CI): m/z 274. Anal. Calcd for C10H8Cl3N3-(0.6 C4H8O2): C, 45.21; H, 3.92; N, 12.76. Found C, 45.37; H, 3.91; N, 12.76.
Reaction SMILES: [Cl:1]CCC(Cl)=O.[NH2:7][C:8]1C=[CH:14][CH:13]=[CH:12][C:9]=1CO.Cl.[NH:17]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][O:21][CH2:20][CH2:19][CH2:18]1>CCOCC.C(N(CC)CC)C.O>[ClH:1].[CH2:18]1[CH2:19][CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:9]4[CH2:8][NH:7][CH2:14][CH2:13][C:12]=4[N:17]1[C:24]=23
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)COCCCN2
Reactant: Nc1ccccc1CO
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: c1cc2c3c(c1)c1c(n3CCCOC2)CCNC1
Temperature: 0 °C

Procedure:
A solution of 2.54 g of β-chloropropionyl chloride in 30 ml of anhydrous ether is added slowly to a stirred solution of 2.13 g of 2-aminobenzyl alcohol in 100 ml of anhydrous ether and 1.8 ml of triethylamine previously cooled to 0° C. After the addition is complete, stirring is continued for another hour, keeping the reaction mixture at 0° C. Water (30 ml.) is then added, and the reaction mixture is acidified with hydrochloric acid. The ether layer is separated, washed with an aqueous saturated solution of sodium chloride, dried with sodium sulfate, filtered and evaporated to dryness. The resulting 2-(2-chloropropionamido)benzyl alcohol is converted, in a manner similar to that described for the preparation of 1,2,3,5-tetrahydro-4,1-benzoxazepine (E. Testa and L. Fontanella, Fr. Pat. No. 1,405,271) to 1,3,4,6-tetrahydro-2H-5,1-benzoxazocine. The latter, by a procedure similaer to that described in Example 110 is converted to the title compound.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C([Li])CCC.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[C:17]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)Cl
Reactant: O=C1CCc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2ccccc2C1=O
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
1-Indanone (1.5 g, 11.36 mmols) was dissolved in dry THF in a three neck flask equipped with nitrogen inlet, septum and a guard tube. The flask was cooled to -20° C. for 10 minutes. Then butyl lithium (11.37 ml, 12.48 mmols) was added dropwise through the septum using the syringe. The reaction mixture was allowed to stand at -20° C. for 45 minutes and then ethyl chloroformate (1.08 ml, 10 mmols) was added dropwise using a syringe. The reaction mixture was stirred at -20° C. for 30 minutes and slowly brought to room temperature in about one hour. The reaction was worked-up by evaporating the THF and the product was chromatographed to yield 2-carbethoxy-1-indanone. NMR: (CDCl3):δ:1.25 (t, 3H, OCH2CH3); 3.45 (d, 2H, benzylic CH2); 3.65 (t, 1H, COCHCO); 4.2 (q, 2H, OCH2CH3); 7.4-7.5 (m, 4H, Ar-H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH:25]=[CH:26][N:14]2[C:13]1=[O:27].S(=O)(=O)(O)O.[CH:33]([OH:35])=[O:34].O>C(OCC)(=O)C.CCCCCC>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH2:25][C@@H:26]([C:33]([OH:35])=[O:34])[N:14]2[C:13]1=[O:27]
Reactant: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)Cc2ccccc2C2CCC=CN12
Reactant: O=CO
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)[C@@H]1CCCC2c3ccccc3CC(N3C(=O)c4ccccc4C3=O)C(=O)N21
Reaction time: 18 h

Procedure:
Combine (S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine (32 mg, 0.09 mmol) and sulfuric acid (1.0 mL, 95-98%) in a pressure vessel. Add 96% formic acid (200 μL) and quickly seal the vessel. After 18 hours, add water (10 mL). Extract the reaction mixture with ethyl acetate. Extract the organic layer with saturated aqueous potassium carbonate solution (5×10 mL). Combine the aqueous layers and carefully acidify with aqueous 12M hydrochloric acid solution. Extract with chloroform (5×15 mL). Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2/1 ethyl acetate/hexane containing 0.5% acetic acid to give the title compound. Rf =0.14 (silica gel, 2/1 ethyl acetate/hexane containing 0.5% acetic acid).
Reaction SMILES: C([N:3](CC)CC)C.Cl[C:9]1[C:14]([NH2:15])=[C:13]([NH:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([CH3:26])=[C:11]([CH3:27])[N:10]=1.[C:28](Cl)(=O)[CH2:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[CH2:31]([C:32]1[N:16]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]2[C:12]([CH3:26])=[C:11]([CH3:27])[N:10]=[C:9]([NH2:3])[C:14]=2[N:15]=1)[CH2:30][CH2:29][CH3:28]
Reactant: Cc1nc(Cl)c(N)c(NCCOc2ccccc2)c1C
Reactant: CCN(CC)CC
Reactant: CCCCC(=O)Cl
Solvent: CC#N
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCOc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.39 ml), anhydrous acetonitrile (100 ml), and 2-chloro-5,6-dimethyl-N4-(2-phenoxyethyl)pyridine-3,4-diamine (2.92 g) from Part A of Example 2 were combined and cooled to 0° C. in an ice bath. Valeryl chloride (0.59 ml) was slowly added to the reaction mixture. After 2 hours, the reaction mixture was heated to 55° C. for 24 hours, at which point HPLC analysis indicated the reaction was complete. The reaction mixture was cooled and the solvent was removed under reduced pressure. The resulting oil was dissolved in dichloromethane and washed with water. The organic layer was dried with magnesium sulfate and the solvent was removed under reduced pressure. The product was then passed through a silica gel column using 50/50 ethyl acetate/hexane as the eluant. The resulting light brown solid was used in the next step.
Reaction SMILES: CC(S[C@@H]1[O:10][C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.[NH:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19].CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO>>[NH:16]1[CH2:23][C@H:22]([OH:10])[CH2:21][C@H:17]1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Temperature: 37 °C
Reaction time: 13 h

Procedure:
A plasmid (pHuCol-Fl, FIG. 6) encoding the gene sequence of the first 80 amino acids of human Type 1 (α1) collagen (FIG. 5) (SEQ. ID. NO. 2) placed behind the isopropyl-β-D-thiogalactopyranoside (IPTG)-inducible tac promotor and also encoding β-lactamase is transformed into Escherichia coli proline auxotrophic strain NM519 (pro−) by standard heat shock transformation. Transformation cultures are plated on Luria Broth (LB) containing 100 μg/mL ampicillin and after overnight growth a single ampicillin-resistant colony is used to inoculate 5 mL of LB containing 100 μg/mL ampicillin. After growth for 10-16 hours with shaking (225 rpm) at 37° C., this culture is used to inoculate 1 L of M9 minimal medium (M9 salts, 2% glucose, 0.01 mg/mL thiamine, 100 μg/mL ampicillin, supplemented with all amino acids at 20 μg/mL except proline which is supplemented at 12.5 mg/L) in a 1.5 L shaker flask. After growth at 37° C., 225 rpm, for 15-20 hours post-inoculation, the optical density at 600 nm is constant at approximately 0.5 OD/mL. The cells are harvested by centrifugation (5000 rpm, 5 minutes), the media decanted, and the cells resuspended in 1 L of M9 minimal media containing 100 μg/mL ampicillin, 0.08M L-hydroxyproline, and 0.5M NaCl. Following growth for 1 hour at 37° C., 225 rpm, IPTG is added to 1 and the cultures allowed to grow for an additional 5-15 hours. Cells are harvested by centrifugation (5000 rpm, 10 minutes) and lysed by mechanical disruption. The hydroxyproline-containing collagen fragment is purified by ammonium sulfate fractionation and column chromatography.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][P+:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12])=O)(C)(C)C.[Br-:38].Cl.C(OCC)C.N>C(Cl)Cl.CO>[CH3:6][NH:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][P+:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:12].[Br-:38]
Reactant: CN(CCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Agent: [Br-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CNCCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109 %

Procedure:
N3-(tert-butoxycarbonyl)-N3-methyl-N-[4-(triphenylphosphonio)butyl]-β-alaninamide bromide (1.08 g, 1.80 mmol) was dissolved in methylene chloride (5.4 mL) and methanol (0.54 mL). The solution at room temperature was treated with 2.0 M hydrogen chloride in diethyl ether (1.98 mL, 3.96 mmol). The mixture was stirred overnight at room temperature, then cooled with an ice bath and treated with 7N ammonia in methanol (0.75 mL, 5.22 mmol). After 30 minutes, the resulting slurry was filtered, and the solids were washed with methylene chloride. The filtrate was concentrated to give the title compound (980 mg, 110%, 84% pure) as a white foam. The product of step 2 was used crude in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[N:4][C:5]1[S:6][CH:7]=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].[N+:14]([O-])([OH:16])=[O:15]>>[CH3:1][N:2]([CH3:13])[CH:3]=[N:4][C:5]1[S:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11]
Reactant: CN(C)C=Nc1scc(Cl)c1C#N
Reactant: O=[N+]([O-])O
Product: CN(C)C=Nc1sc([N+](=O)[O-])c(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
21.3 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-thien-2-yl)-formamidine are introduced into 100 parts of 100% strength nitric acid, while cooling with ice. The mixture is stirred for 1 hour at room temperature, after which the product is precipitated by pouring the mixture onto ice water, and the precipitate formed is filtered off under suction, washed with water and dried to give 18.8 parts (73% of theory) of N,N-dimethyl-N'-(4-chloro-3-cyano-5-nitrothien-2-yl)-formamidine. Decomposition temperature: 254° C. (from glacial acetic acid).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](F)([F:9])=[O:8]>>[C:2]([CH2:3][O:4][C:7]([F:9])=[O:8])([F:6])([F:5])[F:1]
Reactant: O=C(F)F
Reactant: OCC(F)(F)F
Product: O=C(F)OCC(F)(F)F

Procedure:
236faE (CAS Reg. No. 20193-67-3) has been prepared by reaction of 2,2,2-trifluoroethanol with carbonyl fluoride to give the intermediate, CF3CH2OCOF, which was in turn reacted with sulfur tetrafluoride at 150-200° C. to give the product as disclosed by Eisemann in U.S. Pat. No. 3,394,878.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[Cl:29][CH2:30][C:31](Cl)=[O:32].[OH-].[Na+].[Cl-].[Na+]>O.O1CCCC1>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH2:2][NH:1][C:31](=[O:32])[CH2:30][Cl:29])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(Cl)CCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CNC(=O)CCl)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (30.0 g) in water (150 ml) and tetrahydrofuran (450 ml) was added chloroacetyl chloride (6.4 ml) below 10° C., keeping the pH between 8-9 with 4N aqueous sodium hydroxide. The reaction mixture was poured into saturated aqueous sodium chloride (150 ml), the organic layer was separated, and the aqueous solution was extracted twice with ethyl acetate (100 ml). The organic layer was combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give crude (2S,4R)-4-t-butyldimethylsilyloxy-2-(chloroacetamido)methyl-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH:8]([C:15]([NH2:17])=O)[C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH:8]([C:15](=[S:19])[NH2:17])[C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(n1)C(C(N)=O)CCC2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: CC(C)(C)c1ccc2c(n1)C(C(N)=S)CCC2

Procedure:
The title compound was prepared from 2-t-butyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (4 g.) and P2S5 (3 g.) as described in Example 8 and was isolated as creamy needles after recrystallisation from n-hexane m.p. 126° C (650 mgs.). Found: C, 68.18; H, 8.25; N, 11.14%. C14H20N2S requires C,67.70; H, 8.12; N, 11.23%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Br.Br.[CH2:23]([N:30]1[CH2:35][C@@H:34]2[CH2:36][C@H:31]1[CH2:32][NH:33]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:23]([N:30]1[CH2:35][C@@H:34]2[CH2:36][C@H:31]1[CH2:32][N:33]2[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@@H]2C[C@H]1CN2Cc1ccccc1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1S,4S)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (116258-17-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=455.7 [MH+].
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[C:6]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=1)[OH:7].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[OH:7][C:6]1[CH:8]=[C:9]2[C:11]([C:3](=[O:4])[CH2:2][O:10]2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)CCl
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1COc2cc(O)ccc21

Procedure:
Chloroacetyl chloride (28.25 g) was added dropwise over 1.5 hours to a stirred mixture of resorcinol (Aldrich Chemical Company) (22 g), aluminum chloride (33.3 g) and nitrobenzene (250 cc), the temperature being kept at 50°-55° C. during the chloroacetyl chloride addition and for an additional 15 minutes thereafter. The solution was then cooled and poured into an excess of ice and dilute hydrochloric acid. The organic layer was retained and extracted with aqueous sodium hydroxide (300 ml, 1M). The alkaline extract was acidified with concentrated hydrochloric acid and filtered to give 6-hydroxycoumaran-3-one, m.p.--238°-240° C.