Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1.[ClH:11].N([O-])=O.[Na+]>O.[Cu]>[Cl:11][C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1
Reactant: COC(=O)c1nsc(N)n1
Reactant: Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nsc(Cl)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 5-amino-1,2,4-thiadiazole-3-carboxylate (26 g), conc.hydrochloric acid (490 ml) and a small amount of copper was added dropwise over 40 minutes a solution of sodium nitrite (22.5 g) in water (28 ml) at -10° to -15° C. The mixture was stirred for 1.5 hours at the same temperature and for 30 minutes at 50° C. The reaction mixture was poured into ice-water (500 ml) and extracted with ethyl acetate. The extract was washed, dried and concentrated to give white powder of methyl 5-chloro-1,2,4-thiadiazole-3-carboxylate (8.9 g).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:7]1.C([O-])(O)=O.[Na+]>CCO>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([N:8]1[CH2:9][CH2:10][C:11]2[N:1]=[C:2]([NH2:4])[S:3][C:6]=2[CH2:7]1)=[O:21]
Reactant: O=C1CCN(C(=O)c2ccccc2F)CC1Br
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2c(s1)CN(C(=O)c1ccccc1F)CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
Thiourea (0.84 g, 6.7 mmol) was added to a stirred suspension of 3-bromo-1-(2-fluorobenzoyl)-4-piperidinone (2.0 g, 6.7 mmol) and NaHCO3 (0.56 g, 6.7 mmol) in EtOH (50 mL). The mixture was stirred at 80° C. for 2 hours, cooled to room temperature and filtered. The filtrate was evaporated in vacuo to yield 5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-amine (1.0 g, 54% yield) that was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH3:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=O)C.[NH3:28]>CO>[C:24]([O:23][C:21](=[O:22])[N:18]([CH:16]([CH3:17])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][CH:6]([C:4](=[O:3])[NH2:28])[O:7][C:8]=2[CH:14]=1)[CH2:19][CH3:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: N
Reactant: CCOC(=O)C1Oc2ccc(CC(C)N(CC)C(=O)OC(C)(C)C)cc2O1
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc2c(c1)OC(C(N)=O)O2
Reaction time: 1 h
Yield: 96 %

Procedure:
To 2.04 g (5.37 mmol) of 2D was added 30 mL of anhydrous methanol, and ammonia gas was passed through the solution for 1 hour at room temperature. The mixture was concentrated to dryness and the residue purified by silica gel column chromatography using 30% hexane in ethyl acetate to give 1.8 g (5.13 mmol, 96%) of 2E as a colorless gum (M+Na, 373).
Reaction SMILES: [C:1]1([CH:7](Cl)[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[SH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20].C(O)C>O>[C:1]1([CH:7]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=2[O-:20])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(Cl)c1ccccc1
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCCC(Sc1cccc[n+]1[O-])c1ccccc1
Reaction time: 2.5 h

Procedure:
A mixture of 16.9 gms (0.1 mol) of 1-phenylbutylchloride, 36 gms of a 40% aqueous solution of the sodium salt of 2-mercaptopyridine N-oxide (0.1 mol) and 50 ml of ethanol was warmed and stirred at 50° to 60° C. for 2.5 hours. The cooled reaction mixture was poured into 500 ml of water with agitation. The precipitated product was filtered, washed with water and dried. After recrystallization from ethanol a yield of 10 gms (45% theory) of white crystals was obtained.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:14][N:13]=1.IC(C)C.[NH4+].[Cl-]>CS(C)=O>[CH:2]([N:14]1[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][C:12]([C:8]2[S:7][CH:11]=[CH:10][CH:9]=2)=[N:13]1)([CH3:3])[CH3:1]
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CC(C)I
Product: CCOC(=O)c1cc(-c2cccs2)nn1C(C)C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Potassium t-butoxide (0.51 g, 4.5 mmol) was dissolved in DMSO (10 mL) and to this solution was added ethyl 3-(thiophen-2-yl)-1H-pyrazole-5-carboxylate (1.01 g, 4.5 mmol) in small portions and stirred under Ar for 15 min. To this solution was added 2-iodopropane (1.2 g, 6.8 mmol) slowly and stirred for 1 h at RT. Sat. NH4Cl solution was added, the product was extracted with EtOAc (2×40 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography provided ethyl 1-isopropyl-3-(thiophen-2-yl)-1H-pyrazole-5-carboxylate as a pasty mass (0.88 g, 73% yield). 1H NMR (400 MHz, Acetone-d6): δ 7.47 (dd, J=3.2 Hz, 1.2 Hz, 1H), 7.42 (dd, J=4.8 Hz, 1.2 Hz, 1H), 7.12-7.09 (m, 2H), 5.57-5.51 (m, 1H), 4.37 (q, J=7.2 Hz, 2H), 1.50 (d, J=6.8 Hz, 6H), 1.38 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 265.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](Cl)=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.O1CCOCC1.[NH3:26]>ClCCl>[Cl:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([NH2:26])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Reactant: N
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11-chloro-dibenzo[b,f][1,4]thiazepine-3-carbonyl chloride, prepared as described in the previous step, (ca 1.5 mmol) in dichloromethane (10 mL) was treated with a 1,4-dioxane solution of ammonia (0.5 M, 9 mL) under ice bath. The resulting suspension was stirred at room temperature for 1 hour, and the reaction was quenched with water (10 mL). The resulting precipitate was filtered, washed with water and dichloromethane, and dried. The organic layer of the filtrate was washed with saturated aqueous sodium bicarbonate solution and concentrated to additional off white product, which was used in the next step without additional purification. LC-MS: m/z 289 (M+1). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.19 (br, 1H), 8.00-7.96 (m, 2H), 7.90 (d, 1H), 7.64 (br, 1H), 7.56 (m, 1H), 7.47 (m, 1H), 7.31 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3]CC(OC(=O)C)CCCCC.ClCCCC(OC(=O)C)(C)CCCCC.[C:30]([O:33][C:34](C)([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:35][CH2:36][CH2:37][N:38]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51]CC)=[O:50])[S:39]([CH3:42])(=[O:41])=[O:40])(=[O:32])[CH3:31]>>[CH2:2]([CH:48]([CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][N:38]([CH2:37]/[CH:36]=[CH:35]/[CH:34]([O:33][C:30](=[O:32])[CH3:31])[CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[S:39]([CH3:42])(=[O:40])=[O:41])[C:49]([OH:51])=[O:50])[CH3:3]
Reactant: CCCCCC(C)(CCCN(CCCCCCC(=O)OCC)S(C)(=O)=O)OC(C)=O
Reactant: CCCCCC(CCCCl)OC(C)=O
Agent: CCCCCC(C)(CCCCl)OC(C)=O
Product: CCCCCC(/C=C/CN(CCCCCC(CC)C(=O)O)S(C)(=O)=O)OC(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-4-methylnonane (Example S). The product of Step A is thus ethyl 7-[N-(4-acetoxy-4-methylnonyl)methanesulfonamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxy-4-methylnonyl)methanesulfonamido]heptanoic acid (B).
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[N:13]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)[CH:16]=1.[Cl:39][CH2:40][C:41]1[CH:46]=[CH:45][N:44]=[C:43]([C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)[CH:42]=1>>[ClH:39].[ClH:1].[ClH:39].[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[N:13]([CH:33]1[CH2:34][CH2:35][N:36]([CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([C:47]3[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=3)[CH:42]=2)[CH2:37][CH2:38]1)[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)[CH:16]=1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN(c3cccc(OC)c3OC)C3CCNCC3)ccn2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)c4cccc(OC)c4OC)CC3)ccn2)cc(OC)c1OC

Procedure:
4-[N-(2,3-Dimethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride (113 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (59 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as light yellow powder after converting a free base to a trihydrochloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([NH2:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([NH:17][CH:15]([CH3:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CC(C)N)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(CC(C)NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (131 g, 1.15 M) was added during 30 min to a solution of 2-(3-methoxyphenyl)-1-methylethylamine (189.7 g, 1.15 M) and triethylamine (116.7 g, 1.15 M) in benzene (2 l) with cooling to maintain an internal temperature of 20°-30°. The reaction was stirred at room temperature for 2 hr. The benzene solution was filtered from the triethylamine hydrochloride. The filter cake was washed with benzene (500 ml) and the combined filtrates were washed with 1 N. HCl (2×250 ml) and water (2×250 ml). The solution was dried over magnesium sulfate and then evaporated to give the sulfonamide as a thick oil. Wt=292 g.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.[F:14][C:15]1[C:16]([N+:27]([O-:29])=[O:28])=[C:17]([CH:23]=[C:24]([F:26])[CH:25]=1)[O:18][CH2:19][CH:20]1[CH2:22][O:21]1>C(O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]2[CH2:11][CH2:10][N:9]([CH2:22][CH:20]([OH:21])[CH2:19][O:18][C:17]3[CH:23]=[C:24]([F:26])[CH:25]=[C:15]([F:14])[C:16]=3[N+:27]([O-:29])=[O:28])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(OC2CCNC2)cc1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1OCC1CO1
Solvent: CCO
Product: O=[N+]([O-])c1c(F)cc(F)cc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1

Procedure:
A solution of 3-(4-chlorophenoxy)pyrrolidine and 2-[(3,5-difluoro-2-nitrophenoxy)methyl]oxirane (50 mg, 0.21 mmol) in ethanol was refluxed for 3 hrs. The solvent was distilled off under reduced pressure and the resulting residue purified by silica gel column chromatography (dichloromethane/methanol 20:1) to give 45 mg (0.105 mmol) of the title compound as solid.
Reaction SMILES: [C:1]1(=[O:25])[N:5]([CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH:11](CC2C=CC=CC=2)[OH:12])[C:4](=[O:20])[C:3]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:2]12>[Pd].CO.C(O)(=O)C>[C:4]1(=[O:20])[N:5]([CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:1](=[O:25])[C:2]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCNCCC(O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCNCCCO
Reaction time: 3 h
Yield: 84.6 %

Procedure:
N-Phthalimidoethyl(benzyl)-3-amino-1-propanol (4.62 g, 11.95 mmol), Pd/C 10% (1 g) and MeOH:acetic acid (95:5, v/v) (100 mL) was transferred to a 250 mL par hydrogenation flask. The flask was purged and filled with H2 three times and then left under H2 at 55 psi with shaking. The mixture absorbed 20 psi of H2 in 30 minutes. The shaking was stopped and the pressure was raised to 55 psi again. After 3 hrs the pressure was 45 psi so the pressure was increased to 55 psi once more. The reaction was complete as indicated by TLC dichloromethane:MeOH (9:1, v/v) in 4 hours. The reaction mixture was filtered though a bed of celite and the solvent evaporated under vacuo to leave a yellowish oil. The oil was purified by silica gel flash column chromatography using dichloromethane:MeOH (9:1, v/v) as the eluent. The appropriate fractions were combined and concentrated under vacuo to afford 2.51 g (68%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2].N1C=CC(C(O)=O)=C1.[Cl:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:22]([C:21]2[C:20]([Cl:19])=[N:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCOC(=O)c1cc[nH]c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(O)c1cc[nH]c1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]cc1C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a mixture of 1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 14.4 mmol) (synthesized from 1H-pyrrole-3-carboxylic acid suing the same procedure as in Example 30) and 2-chloronicotinoyl chloride (4.4 mg, 25 mmol) in dry benzene (10 mL) at 0° C. was added dropwise a solution of tin (IV) chloride (0.7 g) in dry benzene (5 mL). The mixture was allowed to warm up slowly to room temperature and stirred for overnight. The reaction was diluted with ethyl acetate, washed with brine and concentrated. The residue was purified on a silica gel column to give 402 mg (10%) of 4-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-carboxylic acid ethyl ester.
Reaction SMILES: [Br:1][Si](C)(C)C.[CH3:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH:19]=[C:18]([CH2:21]O)[CH:17]=[CH:16]2>C(Cl)(Cl)Cl>[Br:1][CH2:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][CH:12]=[C:11]2[O:10][CH2:9][CH2:8][O:7][CH3:6])=[CH:16][CH:17]=1
Reactant: COCCOc1cccc2ccc(CO)cc12
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: COCCOc1cccc2ccc(CBr)cc12
Reaction time: 1 h

Procedure:
0.198 ml of bromotrimethylsilane are added dropwise at room temperature to a solution of 0.23 g of [8-(2-methoxyethoxy)naphthalen-2-yl]methanol in 5 ml of chloroform. After 1 hour, the reaction mixture is concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:29]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)[C:28]([CH3:39])=[N:27][N:26]=4)[CH:22]=[CH:21][C:20]=3[CH3:40])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:29]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)[C:28]([CH3:39])=[N:27][N:26]=4)[CH:22]=[CH:21][C:20]=3[CH3:40])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(C)n4Cc4ccc(OC)cc4)ccc3C)csc12
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(C)n4Cc4ccc(OC)cc4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a suspension of 4-chloro-3-{5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.330 g; 0.59 mmol) (from Example 58 supra) in 2-propanol (20 mL) for 15-20 minutes. The mixture was then heated in a microwave reactor at 140° C. for 90 minutes. The reaction mixture was concentrated and the residue was purified by flash chromatography (120 g column; 4% methanol in dichloromethane followed by a gradient to 40% methanol) to give 4-amino-3-{5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.263 g; 96% pure; 78.72%).
Reaction SMILES: C1(N)C=CC(N)=CC=1.C(Cl)(=O)C1C=CC(C([Cl:16])=O)=CC=1.[CH3:21][N:22]1[C:26](=[O:27])[CH2:25]C[CH2:23]1.[Cl-:28].[Cl-].[Ca+2:30]>>[CH3:25][C:26]([N:22]([CH3:23])[CH3:21])=[O:27].[Cl-:16].[Cl-:28].[Ca+2:30]
Reactant: CN1CCCC1=O
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: Nc1ccc(N)cc1
Agent: [Ca+2]
Agent: [Cl-]
Product: CC(=O)N(C)C

Procedure:
In some embodiments, the present invention is related to a process that produces fiber derived from the polymerization of 5(6)-amino-2-(p-aminophenyl)benzimidazole, para-phenylenediamine, and terephthaloyl dichloride at high solids (7 weight percent or greater) in NMP/CaCl2 or DMAC/CaCl2, isolates the copolymer crumb, dissolves the isolated copolymer crumb in concentrated sulfuric acid to form a liquid crystalline solution, and spins the solution into fibers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:34][S:35][C:36]1[O:37][C:38]2[CH:44]=[C:43]([CH:45]=O)[CH:42]=[CH:41][C:39]=2[N:40]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:45][C:43]2[CH:42]=[CH:41][C:39]3[N:40]=[C:36]([S:35][CH3:34])[O:37][C:38]=3[CH:44]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CSc1nc2ccc(C=O)cc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(NCc2ccc3nc(SC)oc3c2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methoxy-2-nitroaniline (500 mg, 2.99 mmol) and TFA (3.07 mL) in DCM (15 mL) at 5° C. was added NaBH(OAc)3 (1.9 g, 8.97 mmol). To the resulting mixture at 0° C. was added a solution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (630 mg, 3.29 mmol) in DCM (10 mL), and. the mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with DCM and washed sequentially with H2O, aq NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 4-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline as a light brown solid (1.08 g, quantitative). 1H NMR (300 MHz, DMSO-d6) δ 8.62 (t, 1H), 7.64 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J=9.3 Hz, 1H), 7.18 (d, J=6.0 Hz, 1H), 6.93 (d, J=9.3 Hz, 1H), 4.71 (d, J=5.7 Hz, 1H), 3.72 (s, 3H), 2.75 (s, 3H). LCMS (ESI) m/z 346 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:27][S:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[N:11]1[CH:7]([C:5]2[S:6][C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:28][CH3:27])[CH:34]=3)=[CH:3][CH:4]=2)[CH2:8][C:9]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[N:10]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(Br)s2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CSc1cccc(-c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
5-(5-Bromo-thiophen-2-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 8 of Preparation 13, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (12.5 mg, cat.) and a 2N sodium carbonate solution (500.0 uL) were added to a mixed solvent of ethanol (500.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 15.0 mg of the titled compound as a white liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([F:21])[CH:15]=1)[OH:13])[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.CS(Cl)(=O)=O.CCC([O-])(C)C.[K+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:7]1[CH2:8][CH2:9][O:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([F:21])[CH:15]=2)[CH2:11]1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Br)c(F)c1
Agent: CCC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
[2-(4-Bromo-3-fluoro-phenyl)-2-hydroxy-ethyl]-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester (25.3 g, 66.9 mmol) and triuethylamine (10.2 g, 14.0 ml, 100 mmol) were combined with tetrahydrofurane (270 ml) to give a light yellow solution. The reaction mixture was cooled to 0-5° C. and methanesulfonyl chloride (8.43 g, 5.73 ml, 73.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h to give a white suspension. The reaction mixture was filtered and washed with tetrahydrofurane (20 ml). Potassium 2-methyl-2-butoxide (1.7 M in toluene, 59 ml, 100 mmol) was added dropwise to the filtrate at 0-5° C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ethyl acetate and extracted with dilute aqueous hydrochloric acid (pH 5), water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give a yellow oil which was further purified by flash chromatography (silica gel, heptane/ethyl acetate 4:1): yellow solid (19.5 g, 81%), MS (ISP): 259.9 ([{79Br}M-BOC+H]+), 261.9 ([{81Br}M-BOC+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18]CN(C(C)C)C(C)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)CC1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(tert-Butoxycarbonyl)azepane-4-carboxylic acid (1.0 g; 4.11 mmol) in DCM (20 ml) and treated with DIPEA (1.5 ml, 8.22 mmol) followed by trimethyloxonium tetrafluoroborate (790 mg, 5.34 mmol) in DCM (5 ml). The mixture was stirred at RT for 3 hours and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic portion was separated and the aqueous was further extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound which was used without further purification.