Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=[C:5]1[C:9](=[O:10])[O:8][C:7]([CH3:11])=[N:6]1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:9](=[O:10])/[C:5](/[NH:6][C:7](=[O:8])[CH3:11])=[CH:4]/[CH2:3][O:2][CH3:1]
Reactant: COCC=C1N=C(C)OC1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC/C=C(\NC(C)=O)C(=O)OC

Procedure:
A solution consisting of 19 g (0.165 mol) of oxazolones 3 and 100 ml of methanol was treated with solid sodium methoxide until the reaction mixture was slightly basic (pH 9 as indicated by moist pH paper). The solution was stirred for 3/4 hr. at room temperature. The reaction mixture was concentrated in vacuo, and the residue taken up in 500 ml of ether. Petroleum ether (bp 35°-60°) was added until the solution was slightly turbid. An additional portion of ether was added to clear the turbidity and the resultant solution was treated with charcoal and filtered through Celite®. The solvents were removed in vacuo, and the residue dried at 0.1 mm. Crystallization from ether/petroleum ether (bp 35°-60°) yielded Z-2-acetamido-4-methoxy-2-butenoic acid methyl ester (4): mp 60°-61°; IR (CHCl3) 3415, 1720, 1700, 1500 cm-1 ; UV (EtOH) λmax 226 nm (ε7500); NMR (CDCl3) δ 7.5 (broad, 1H, NH), 6.7 (t, 1H, --CH2CH=), 4.1 (d, 2H, --CH2CH=), 3.8 (s, 3H, CH3O2C--), 3.4 (s, 3H, CH3OCH2 --), 2.14 (s, 3H, CH3CONH--). (Calcd. for C8H13NO4 : C, 51.33; H, 7.00; N, 7.48. Found: C, 51.20; H, 7.13; N, 7.69.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O[CH:32](OCC)[CH2:33][CH:34](OCC)OCC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]3[N:28]=[CH:34][CH:33]=[CH:32][N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCC(=N)N)CCC2c2ccc(F)cc2)cc1
Reactant: CCOC(CC(OCC)OCC)OCC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C(CCCc3ncccn3)CCC2c2ccc(F)cc2)cc1
Yield: 20 %

Procedure:
A stirred solution of (2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-butyramidine (0.33 g, 0.82 mmol) in 1,1,3,3-tetraethoxy-propane (7 ml) and DMF (1.5 ml) was heated for 1 h at 150° C. Evaporation and purification by column chromatography on silica gel (dichloromethane/MeOH 98:2) yielded the title compound (73 mg, 20%) as a light brown oil, MS: m/e=440.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1/[CH:1]=[CH:23]/[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: Cc1nc2ccccc2n1-c1ccccn1
Reactant: O=Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccn1
Temperature: 80 °C
Yield: 25.2 %

Procedure:
A stirred mixture of 2-methyl-1-(2-pyridyl)-1H-benzimidazole (0.50 g, 2.39), pyridine-2-carboxaldehyde (0.50 g, 4.67 mmol) and acetic anhydride (5 ml) was heated to 80° C. for 1.5 h and then to reflux for about 6 h. After cooling, the mixture was diluted with water (15 ml), basified with a 10% aqueous solution of sodium hydroxide (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were washed with water (100 ml) and extracted with 2 N hydrochloric acid (3×50 ml). The combined aqueous extracts were basified with a 50% aqueous solution of sodium hydroxide (3×50 ml) and extracted with dichloromethane (4×50 ml). The combined organic extracts were washed consecutively with water (100 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to dryness. Column chromatography (silica gel, 125 g; ethyl acetate) gave 0.18 g of free base (E)-1-(2-pyridyl)-2-[2-(2-pyridyl)ethenyl]-1H-benzimidazole as a brown oil. This product was dissolved into methanol (5 ml), treated with a 10% methanol solution of hydrogen chloride (5 ml) and concentrated to dryness. Recrystallization from 2-propanol afforded 0.15 g (21%) of the titled compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10]C)[CH:5]=1.C(Cl)(Cl)Cl.B(Br)(Br)Br.[NH4+].[OH-]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(CCBr)c1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Oc1cccc(CCBr)c1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2-bromoethyl)-3-methoxybenzene (1.00 g, 4.7 mmol) in CHCl3 (50 mL, 0.6 mol) was cooled to at 0° C. 1.0 M of BBr3 in DCM (27.9 mL) was cooled to 0° C. and added to the solution. The solution was allowed to warm to 30° C. over 30 minutes, then was poured into a solution of ice and 30% NH4OH, which was stirred at 0° C. for 30 minutes. The organic layer was taken and concentrated with no reduced pressure.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[N:11]2)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[NH:34])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][O:16][C:12]1[CH:13]=[CH:14][C:15]2[N:10]([N:9]=[CH:8][C:7]=2[C:5]2[CH:4]=[CH:3][N:35]=[C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)=[CH:31][CH:30]=3)[N:34]=2)[N:11]=1
Reactant: COc1ccc2c(C(=O)/C=C/N(C)C)cnn2n1
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccnc(Nc4ccc(N5CCN(C)CC5)cc4)n3)cnn2n1
Temperature: 130 °C
Yield: 18 %

Procedure:
To a solution (2E)-3-(dimethylamino)-1-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one (40 mg, 0.16 mmol) in DMF (2.0 mL) was added N-[4-(4-methyl-1-piperazinyl)phenyl]guanidine.HCl (99 mg, 0.32 mmol) and potassium carbonate (112 mg, 0.80 mmol). The reaction was heated at an oil bath temperature of 130° C. for about 18 hours. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in chloroform and filtered. The filtrate was concentrated in vacuo then disolved in CH2Cl2 and triturated with diethylether to give the title compound as a yellow solid (12 mg, 18%). 1H-NMR (400 MHz, CDCl3) δ 8.67 (d, 1H, J=9.5 Hz), 8.35 (d, 1H, J=5.2 Hz), 8.29 (s, 1H), 7.46 (d, 2H, J=8.9 Hz), 6.98 (m, 3H), 6.90 (s, 1H), 6.75 (d, 1H, J=9.5 Hz), 4.09 (s, 3H), 3.23 (m, 4H), 2.64 (m, 4H), 2.39 (s, 3H); MS (ESI) (M+H)+ 417.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([CH2:29]O)[CH:25]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11](=[O:22])[N:12]([CH2:29][C:26]3[CH:25]=[C:24]([CH3:23])[O:28][N:27]=3)[C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: Cc1cc(CO)no1
Reactant: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3cc(C)on3)C2=O)cc1
Temperature: 130 °C
Yield: 21.1 %

Procedure:
To a solution of 3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione (0.17 mmol, 50 mg), 5-methylisoxazole-3-methanol (0.19 mmol, 21 mg) and diethyl azodicarboxylate (0.19 mmol, 33 mg) in dry THF (1 mL) was added triphenylphosphine (0.19 mmol, 49 mg) in dry THF (1 mL). The mixture was heated in a microwave reactor at 130° C. for six min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 14 mg (21%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.23 (bs, 1H), 7.16-7.06 (m, 3H), 7.01-6.96 (m, 2H), 6.63-6.53 (m, 4H), 6.03 (d, J=0.7 Hz, 1H), 4.82 (s, 2H), 3.70 (s, 3H), 2.39 (d, J=0.7 Hz, 3H).
Reaction SMILES: [CH2:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([NH:14]C(=O)C(F)(F)F)[CH:11]=[CH:10][C:9]=1[S:21](Cl)(=[O:23])=[O:22])(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1.N1C=CC=CC=1>C(#N)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([S:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:33][O:32][B:31]([OH:34])[C:30]=3[CH:35]=2)(=[O:22])=[O:23])=[C:8]([CH2:7][S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6])[CH:13]=1
Reactant: CCCS(=O)(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCS(=O)(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.3 %

Procedure:
To a stirred solution of 2-(propylsulfonylmethyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (700 mg, 1.7 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (384 mg, 2.58 mmol) in 10 mL of ACN was added pyridine (278 uL, 3.4 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. A solution of this crude compound in 7M ammonium in MeOH (10 mL) was stirred in a sealed tube at 50° C. for 4 hours. After concentrated, the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as an off-white solid (428 mg, yield 59%). MS calcd for (C17H21BN2O6S2): 424.3. MS found (ESI negative): (M−H)−=423.1. 1H NMR (DMSO-d6) δ (ppm): 9.88 (s, 1H), 9.20 (bs, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.73 (s, 1H), 6.47 (d, J=8.4 Hz, 1H), 4.86 (s, 2H), 4.69 (s, 2H), 2.97 (t, 2H), 1.61 (m, 2H), 0.89 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.Cl[C:12]([O:14][CH:15]=[CH2:16])=[O:13]>CCOCC>[C:12](=[O:13])([O:14][CH:15]=[CH2:16])[O:4][CH2:3][CH2:2][Br:1]
Reactant: C=COC(=O)Cl
Reactant: OCCBr
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=COC(=O)OCCBr
Temperature: 25 °C
Reaction time: 27 h
Yield: 78.8 %

Procedure:
To a 1L 4-neck round bottom flask fitted with a mechanical stirrer, thermometer, condenser, dropping funnel and nitrogen blanket was added 31.2 g (250 mmol) of 2-bromoethanol, 21.4 g (270 mmol) of pyridine and 400 mL of ether. The reaction was cooled with an ice-water bath to less than 10° C. then 28.8 g (270 mmol) of vinyl chloroformate was added so that the temperature remained below 10° C. The reaction was stirred to room temperature for 27 hours. Then the organics were washed twice with 2N HCl, twice with 2N NaOH, then dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting oil was passed through a short silica gel column, to remove most of the color, to give 38.4 g (197 mmol, 78.8% yield). FTIR (neat, capillary) 3672.76, 3469.03, 3096.75, 2972.97, 2155.40, 2057.14, 1754.37, 1648.44, 1563.96, 1455.87, 1443.36, 1427.17, 1388.17, 1299.17,.1285.60, 1244.29, 1221.29, 1152.23, 1095.86, 1049.38, 988.10, 940.93, 897.08, 875.78, 828.81, 778.74, 738.01, 694.54, 663.28. NMR (CDCl3) 6.85-7.23 (1H,q), 4.40-5.10 (4H,m), 3.42-3.59(2H,t).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[N:4]=[C:13]=[O:14]
Reactant: COc1cc(N)c(Cl)cc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)c(Cl)cc1F
Yield: 175.1 %

Procedure:
In the manner of Example 2, Step D, the reaction of 3.0 g (0.017 mole) of 2-chloro-4-fluoro-5-methoxyaniline with 1.68 g (0.0085 mole) of trichloromethyl chloroformate in 20 mL of toluene produced 3.0 g of 2-chloro-4-fluoro-5-methoxyphenyl isocyanate.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]([C:14]#[C:15][C:16](OC)=[O:17])=[O:13]>>[CH3:1][S:2][C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:14]([C:12]([O:11][CH3:10])=[O:13])=[CH:15][C:16]2=[O:17]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CSc1ccc(N)cc1
Product: COC(=O)c1cc(=O)c2cc(SC)ccc2[nH]1
Yield: 28.5 %

Procedure:
Using the method described in Example 18a with 4-methylthioaniline (20 g) and dimethyl-acetylene dicarboxylate (20.21 g) as reagents gave methyl 6-methylthio-4-oxo-1,4-dihydroquinoline-2-carboxylate (10.12 g), m.p. 264°-266° C. δ (360 MHz, DMSO-d6), 2.55 (3H, s, CH3S), 3.96 (3H, s, CH3O), 6.68 (1H, s, 3-H), 7.64 (1H, dd, 7-H), 7.83 (1H, d, 5-H) and 7.89 (1H, d, 8-H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:9][N:10]([CH2:12][CH2:13]O)[CH3:11]>>[C:1]([O:8][CH2:13][CH2:12][N:10]([CH3:11])[CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O:6][CH2:13][CH2:12][N:10]([CH3:11])[CH3:9])=[O:5]
Reactant: O=C(O)CCC(=O)O
Reactant: CN(C)CCO
Product: CN(C)CCOC(=O)CCC(=O)OCCN(C)C

Procedure:
In method I succinic acid is reacted with dimethylaminoethanol to give bis(2-dimethylaminoethyl) succinate, which is then reacted with methyl chloride to give succinylcholine chloride.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.Cl([O-])(=O)(=O)=O.[CH2:22]1[C:29]2[CH2:28][CH2:27][CH2:26][N+:25]=2[CH2:24][CH2:23]1.Cl>C1COCC1.CCOC(C)=O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:29]23[CH2:28][CH2:27][CH2:26][N:25]2[CH2:24][CH2:23][CH2:22]3)[CH:8]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C1CC2=[N+](C1)CCC2
Agent: Cl
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc2ncc(C34CCCN3CCC4)cc2c1
Temperature: -100 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A solution of 2.5M nBuLi (1.2 mL, 2.8 mmol) in hexanes was added to 3-bromoquinoline (386 μL, 2.8 mmol) in THF (10 mL) at -100° C. followed immediately by 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (200 mg, 0.9 mmol). The reaction mixture was allowed to stir for 2 hours at -100° C. and then 2N HCl was added at 0° C. After warming to ambient temperature, the mixture was poured over EtOAc and the phases were separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (3×). The organic fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; EtOAc) to afford a pale solid (104 mg, 46%). mp 80°-83° C. MS (CI/NH3) m/e: 239 (M+H)+. 1 H NMR (CDCl3, 300 MHz) δ1.61-1.75 (m, 2H), 1.83-1.94 (m, 2H), 2.03-2.17 (m, 4H), 2.71-2.80 (m, 2H), 3.20-3.27 (m, 2H), 7.52 (ddd, J=7.0, 7.0, 1.1 Hz, 1H), 7.65 (ddd, J=7.0, 7.0, 1.5 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 8.32 (d, J=2.2, Hz, 1H), 8.97 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.[C:10](OCC)(=[O:12])C>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([N:5]=[C:10]=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(C)=O
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCOCC
Product: O=C=Nc1cccc(Br)c1
Yield: 87 %

Procedure:
3-Bromoaniline (2.63 g, 15.3 mmol) was dissolved in ethyl acetate (100 ml) and 1N dry hydrogen chloride in diethyl ether (15.3 ml) was added and the solvents were removed in vacuo. The residue was stripped twice with toluene and the residue was suspended in toluene (30 ml). Diphosgene (6.1 ml) was added and the mixture was refluxed for 1.5 hour. After cooling, the solution was concentrated in vacuo to afford 2.63 g (87%) 3-bromophenyliso-cyanate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH2:8][OH:9].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:18][C:19](=[O:20])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:5]2=[N:6][C:7]=1[CH2:8][OH:9]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCc1nc2nc(CO)c(Br)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc2cc(Br)c(CO)nc2n1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
10 g(0.0352 mole) of the compound obtained in step 6, 7.59 g(0.0387 mole) of 2-bromoacetophenone and 9.8 g(0.0704 mole) of K2CO3 were dissolved in 50 ml of dimethyl formamide. The reaction solution was stirred for 3 hours at room temperature, diluted with 200 ml of ethyl acetate and washed with water(100 ml×3). The organic layer was dried over Na2SO4 and purified with column chromatography(silica gel, methylene chloride:ethyl acetate =1:1) to obtain 6.96 g of the title compound(yield 64%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[CH:16]1[O:20][N:19]=[C:18]([C:21](=O)[CH2:22]Cl)[CH2:17]1)(=[O:4])=[O:3].[C:25]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)(=[S:27])[NH2:26].O>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][C:7]=1[CH:16]1[O:20][N:19]=[C:18]([C:21]2[N:26]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[S:27][CH:22]=2)[CH2:17]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1cc(C(F)(F)F)ccc1C1CC(C(=O)CCl)=NO1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccc(C(F)(F)F)cc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of 2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]-5-(trifluoromethyl)phenyl methanesulphonate (200 mg) and tert-butyl 4-carbamothioylpiperidine-1-carboxylate (108 mg) in tetrahydrofuran (2 ml) at room temperature was added tetrabutylammonium bromide. The reaction mixture was stirred at room temperature for 12 hours. Then water was added thereto, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave tert-butyl 4-[4-(5-{2-[(methylsulphonyl)oxy]-4-(trifluoromethyl)phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (168 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:10]2[CH:14]=[CH:13][C:12]([CH3:15])=[N:11]2)[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([N:10]2[CH:14]=[CH:13][C:12]([CH3:15])=[N:11]2)[CH:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2C=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccn(-c2cc(Cl)ccc2CO)n1
Temperature: 0 °C

Procedure:
4-Chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde (446 mg, 2.03 mmol) from Step 1 was dissolved in MeOH (14 mL) and cooled to 0° C. NaBH4 (175 mg, 4.61 mmol)) was added portionwise. The reaction mixture was allowed to warm to RT, and after 90 min was quenched with acetone. The MeOH was removed in vacuo. The residue was partitioned between water and EtOAc and then extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH3:27][Sn](C)(C)C>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:27])[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C)c2c(c1O)c1ccccc1n2-c1ccccc1
Temperature: 120 °C
Reaction time: 0.83 h

Procedure:
A mixture of 1-bromo-4-hydroxy-9-phenyl-9H-b-carboline-3-carboxylic acid ethyl ester (78 mg, 0.19 mmol), tetramethyltin (37 mg, 0.21 mmol), and Pd(PPh3)2Cl2 (6.7 mg, 0.0095 mmol) in DMF (1 mL) was stirred at 120° C. for 50 min. The mixture was then diluted with EtOAc, washed with water and saturated NaCl aqueous solution, respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column to give a white solid, the desired title compound. The title compound, ESI MS (m/z): 347 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+].Cl>C(O)C>[CH2:18]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:3][C:2]=1[F:1])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCBr
Reactant: O=C(O)c1ccc(-c2ccc(O)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1F

Procedure:
The resulting 3'-fluoro-4'-hydroxybiphenyl-4-carboxylic acid was heated under reflux for 10 hours in hydrous ethanol together with 1.2 moles, per mole of the carboxylic acid, of decyl bromide and 1.95 moles, per mole of the carboxylic acid, of sodium hydroxide. Then, 10% hydrochloric acid was added to adjust the pH of the solution to 2 to 3. The solution was then heated under reflux for 1 hour. After cooling, the organic materials were extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform layer was concentrated to obtain crude crystals. Recrystallization from ethanol gave the desired 4'-decyloxy-3'-fluorobiphenyl-4-carboxylic acid. The yield in this alkoxylation reaction slightly varies depending upon the type of the alkyl bromide used, but it is generally 60 to 80%.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:22]=1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: N#Cc1ccc(Cl)cc1N
Product: N#Cc1ccc(Cl)cc1S(=O)(=O)Cl

Procedure:
The titled compound is prepared analogously 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 2-amino-4-chloro-benzonitrile.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:5][CH:4]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21])[CH:2]=1.[Na].[OH-].[Na+:34]>CCO>[CH:5]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:1][CH:2]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:4]=1.[Na+:34].[Na+:34]
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)O)C(=O)O)cc3)c2c(=O)[nH]1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)[O-])C(=O)[O-])cc3)c2c(=O)[nH]1

Procedure:
A suspension of Pemetrexed Monosodium in EtOH containing 0-2% water (v/v) was heated to reflux. 1.0 eq of aq. NaOH (30% w/w) were added over a period of 2 to 4 h and the mixture was stirred under reflux until PXRD showed complete conversion. The suspension was cooled to 20° C. to 30° C. and the solid was isolated by filtration, washed with EtOH and dried in vacuo to constant weight at 50° C. at 5 mbar to give Pemetrexed Disodium Form IV.