Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)[OH:13])=[CH:8][CH:7]=1.[OH-].[Na+].C1(C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O>C(#N)C>[CH2:1]([N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[C:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:13])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: OC(c1ccccc1)(c1ccc(Cl)cc1)c1ncc[nH]1
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C=CCn1ccnc1C(O)(c1ccccc1)c1ccc(Cl)cc1

Procedure:
A mixture of 3.4 g (0.028 mol) of freshly distilled allyl bromide, 7 g (0.025 mol) of α-(p-chlorophenyl)-α-phenylimidazole-2-methanol (prepared according to Example IV), 1.2 g (0.030 mol) of sodium hydroxide, 0.050 g of picric acid and 50 ml. of acetonitrile was refluxed for 5 hours. The warm reaction mixture was filtered and water was added to the filtrate. The precipitate formed was filtered off, washed with water and petroleum ether (boiling range 40°-60° C.) and three times crystallised from isopropyl alcohol. 1-Allyl-α-(p-chlorophenyl)-α-phenylimidazole-2-methanol was obtained. Melting point 165°-165.5° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:8]=1
Reactant: O=C1CCC(=O)C1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CNC[C@H]2CC[C@@H]1O[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2CC[C@@H]1O[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from (3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(tri-fluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)octahydro-1H-isoindole (step L) and cyclopentane-1,3-dione according to the procedure of Example 7. 1H-NMR (CDCl3): rotamers δ: 7.64 (1H, s), 7.18 (2H, s), 7.04-6.97 (4H, m), 4.74, 4.53 (1H, s), 4.42 (1H, m), 3.68, 3.43 (1H, m), 3.50 (1H, m), 3.06 (1H, m), 2.93 (2H, m), 2.86, 2.76 (1H, m), 2.57 (1H, m), 2.40 (2H, m), 2.28 (3H, s), 2.20 (1H, m), 2.17 (1H, m), 2.10-1.94 (3H, m), 1.58 (1H, m), 1.40 (1H, m), 1.28 (3H, d, J=6.0 Hz). MS: (MH)+552.43
Reaction SMILES: [CH2:1]([C:3]1([OH:17])[C:13]2[C:8](=[C:9]([O:14]C)[N:10]=[CH:11][CH:12]=2)[CH2:7][O:6][C:5](=[O:16])[CH2:4]1)[CH3:2]>Cl>[CH2:1]([C:3]1([OH:17])[C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:14])[C:8]=2[CH2:7][O:6][C:5](=[O:16])[CH2:4]1)[CH3:2]
Reactant: CCC1(O)CC(=O)OCc2c1ccnc2OC
Agent: Cl
Product: CCC1(O)CC(=O)OCc2c1cc[nH]c2=O
Reaction time: 8 h
Yield: 49.1 %

Procedure:
5-Ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino [3,4-c]pyridin-3(1H)-one (0.5 g, 2.1 mmol) is heated under reflux for 9 hours in 1N hydrochloric acid (20 ml). The reaction mixture is concentrated under reduced pressure and the residue is again dried by the addition and evaporation of toluene twice, then left overnight under reduced pressure in the presence of phosphorus pentoxide. The resultant oil is dissolved in anhydrous acetonitrile (5 ml) and agitated under argon for 24 hours. The precipitate is filtered out and dried, which produces 0.23 g (49%) of a white solid (M), m.p. 118-119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:24])[C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(-c2ccc(F)cc2)c2ccccc2n1C
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
To a solution of 8.0 g. (28 mmol.) of ethyl 3-(4'-fluorophenyl)indole-2-carboxylate in 30 ml. of dry dimethylacetamide stirred under nitrogen at -10° C., 1.6 g. (33 mmol.) of sodium hydride is added. The reaction mixture is stirred at -10° C. under nitrogen for 45 min., 4.8 g. (32 mmol.) of methyl iodide is added at -10° C., and the reaction mixture is allowed to warm to room temperature and stirred under nitrogen at room temperature for 2 hrs. The reaction mixture is poured into 400 ml. of ice/water, neutralized with 4 ml. of 2N. hydrochloric acid and extracted several times with diethyl ether. The diethyl ether extracts are combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure. The residue is purified by column chromatography utilizing a silica gel column and chloroform as the eluant. The fractions containing the product are combined and evaporated at reduced pressure, and the residue is crystallized from n-hexane/petroleum ether to obtain the product (7.6 g. (91%)), m.p. 61°-62° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:47]([O:51][C:52]([N:54]1[C@@H:59]([CH3:60])[CH2:58][NH:57][CH2:56][C@H:55]1[CH3:61])=[O:53])([CH3:50])([CH3:49])[CH3:48]>CS(C)=O>[C:47]([O:51][C:52]([N:54]1[C@@H:59]([CH3:60])[CH2:58][N:57]([C:2]2[CH:7]=[N:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][C:13]4[NH:16][C:17]([C:19]5[C:27]6[C:22](=[CH:23][C:24]([C:28]7[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=7[CH2:36][CH3:37])=[CH:25][CH:26]=6)[NH:21][N:20]=5)=[N:18][C:12]=4[CH2:11]3)=[O:9])=[CH:4][N:3]=2)[CH2:56][C@H:55]1[CH3:61])=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C5)cn3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (150 mg, 0.154 mmol) in DMSO (1.5 mL) were added DIPEA (0.143 mL, 0.87 mmol) and (2R,6S)-2,6-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester (124 mg, 0.58 mmol) and the mixture stirred at room temperature for 18 hours. The crude reaction mass was purified by prep-HPLC Method F to afford (3R,5S)-5′-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1H-indazol-3-yl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carbonyl}-3,5-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester as an off white solid (80 mg, 40%).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:71])([C:67]([F:70])([F:69])[F:68])[C:24]([F:66])([F:65])[C:25]([F:64])([F:63])[O:26][C:27]([F:62])([F:61])[C:28]([F:60])([F:59])[O:29][C:30]([F:58])([F:57])[C:31]([F:56])([F:55])[C:32]([F:54])([F:53])[C:33]([F:52])([F:51])[C:34]([F:50])([F:49])[CH2:35][O:36][CH2:37][CH2:38]S(C1C=CC(C)=CC=1)(=O)=O.C1(=O)OCCO1.FC(F)(C(F)(F)F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CO.CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][CH2:37][O:36][CH2:35][C:34]([F:49])([F:50])[C:33]([F:51])([F:52])[C:32]([F:53])([F:54])[C:31]([F:55])([F:56])[C:30]([O:29][C:28]([F:59])([F:60])[C:27]([F:61])([F:62])[O:26][C:25]([F:63])([F:64])[C:24]([F:66])([F:65])[C:23]([F:22])([F:71])[C:67]([F:70])([F:69])[F:68])([F:58])[F:57])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1ccc(S(=O)(=O)CCOCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O=C1OCCO1
Product: CCCCCCCCc1cnc(-c2ccc(OCCOCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.04 g, 3.64 mmol) and 2-(6-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2,3,3,4,4,5,5,6,6-decafluorohexyloxy)-1-p-toluenesulfonyl ethane (3.36 g, 4.05 mmol; prepared by combining ethylene carbonate and 6-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2,3,3,4,4,5,5,6,6-decafluorohexanol and then preparing the p-toluenesulfonate from p-toluenesulfonyl chloride. The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with ethyl acetate/hexane, to yield 2.88 g of purified product.
Reaction SMILES: [SH:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=2)=[N:4][N:3]=1.Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>>[C:29]([C:28]1[CH:27]=[C:26]([CH:33]=[CH:32][CH:31]=1)[CH2:25][S:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[N:4][N:3]=1)#[N:30]
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=C(CCc1ccccc1)Nc1cc(-c2nnc(S)o2)ccn1
Product: N#Cc1cccc(CSc2nnc(-c3ccnc(NC(=O)CCc4ccccc4)c3)o2)c1
Yield: 36 %

Procedure:
In the same manner as in Example 1 and using N-[4-(5-mercapto-1,3,4-oxadiazol-2-yl)-2-pyridyl]-3-phenylpropionamide instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 36%) was obtained as colorless crystals.
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[CH2:29]([OH:34])[CH2:30][CH2:31][C:32]#[CH:33].[Cl-].C(#N)C>C(N(CC)CC)C.[Cu]I>[OH:34][CH2:29][CH2:30][CH2:31][C:32]#[C:33][C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Reactant: C#CCCCO
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCCO)n(Cc3cccc4ccccc34)cc21
Temperature: 25 °C

Procedure:
5-Iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo-[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg), 4-pentyn-1-ol (0.080 ml), bis-triphenylphosphinepalladium (II) chloride (3 mg) and copper (I) iodide (1 mg) were dissolved in triethylamine (3 ml) and acetonitrile (1 ml) and heated to 90° C. in a sealed pressure tube for 3 hours. The reaction mixture was allowed to cool to room temperature and was then evaporated to leave a residue which was recrystallised from ethyl acetate. The resultant brown solid was chromatographed, eluting with ethyl acetate to give a white solid which was triturated with ethyl acetate to give the title compound (45 mg). Melting point: 176-177° C. MS (APCI+ve) 444 (M+H)+ 1H NMR (CDCl3) δ 0.84 (d, 6H), 1.82 (m, 2H), 2.08 (m, 1H), 2.36 (t, 1H), 2.65 (t, 2H), 3.40 (s, 3H), 3.50 (d, 2H), 3.77 (q, 2H), 5.67 (s, 2H), 6.10 (s, 1H), 7.08 (d, 1H), 7.47 (dd, 1H), 7.55 (m, 2H), 7.86-7.94 (m, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:37]([C:34]4[CH:35]=[CH:36][N:31]=[N:32][CH:33]=4)=[O:38])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: O=C(O)c1ccnnc1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3ccnnc3)CC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with pyridazine-4-carboxylic acid to yield the title compound as light yellow solid. MS: 533.2 (MH+, 1Cl).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5](COCC[Si](C)(C)C)[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:27]4[CH:28]=[C:29]([CH2:31][CH2:32][C:33]5[CH:42]=[CH:41][C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=5)[N:30]=[C:26]4[C:25]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:6](=[O:7])[NH:5][C:4]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:27]4[CH:28]=[C:29]([CH2:31][CH2:32][C:33]5[CH:42]=[CH:41][C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=5)[N:30]=[C:26]4[C:25]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)=[N:24][CH:23]=3)=[CH:20][CH:21]=2)=[N:3]1
Reactant: Cn1nc(-c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2)n(COCC[Si](C)(C)C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2)[nH]c1=O
Temperature: 0 °C
Yield: 25.5 %

Procedure:
To a solution of compound 10e (200 mg, 0.290 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise with stirring at 0° C. The resulting solution was stirred at rt overnight. The reaction was quenched with MeOH (10 mL). The resulting solids were collected by filtration and washed with Et2O, and then suspended in MeOH (10 mL) and DIPEA (0.5 mL). The mixture was stirred at 70° C. for 30 min. After cooling to rt, the solids were collected by filtration and washed with Et2O to obtain the title compound 33 as a light yellow solid (39.4 mg, 24% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 12.36 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.95-7.88 (m, 4H), 7.75-7.68 (m, 4H), 7.58-7.49 (m, 2H), 7.41 (s, 1H), 4.20-4.08 (m, 4H), 3.75-3.65 (m, 4H), 3.41 (s, 3H), 3.40-3.25 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H28N8O2: 533.2 (M+H). Found 533.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:9][C:3]1[C:2]([NH:1][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([Cl:8])[N:6]=[CH:5][N:4]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1c(Cl)ncnc1Cl)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 5-amino-4,6-dichloropyrimidine (1.15 g, 0.00701 mol) and benzoyl chloride (1.0 mL, 0.0086 mol) was heated at 100° C. overnight. The reaction was cooled and the residue was triturated with diethyl ether, filtered and collected to obtain 1.6 g (85%).
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
Reaction time: 2 h

Procedure:
A suspension of Pemetrexed Monosodium in EtOH containing 0-2% water (v/v) was heated to reflux and 0.85 eq of aq. NaOH (30% w/w) were added. The mixture was stirred at reflux until PXRD showed complete conversion. 0.15 eq of aq. NaOH (30% w/w) were added and stirring under reflux was continued for 2 h before the suspension was cooled to 20° C. to 30° C. Pemetrexed Disodium Form IV was isolated by filtration, washed with EtOH and dried in vacuo at 50° C. at 5 mbar to constant weight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:17]=1[CH2:26][C:27](O)=[O:28]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:17]2[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:16]=2[O:15][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(CC(=O)O)c(OC)c1OC
Product: COc1ccc(CCNC(=O)Cc2ccc(OC)c(OC)c2OC)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine and 2,3,4-trimethoxyphenylacetic acid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N+:24]([O-])=O)[CH:3]=1.Cl.Cl[Sn]Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([NH2:24])[CH:3]=1
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: Cc1c(Cn2c(C)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 4-bromo-2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (55 g, 129 mmol) in methanol (600 mL) was added conc. HCl (20 mL), SnCl2 (174 g, 771 mmol) and the mixture was stirred at 70° C. for 2 h. Then the solvent was removed in vacuo, and the residue was diluted with 1N Na2CO3 solution (1.5 L) and extracted with DCM (200 mL×5). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated to give the crude product (45 g, 88%) as a white solid; LC/MS: MS (ES+) m/e 398 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.37 (s, 3H), 2.52 (s, 3H), 5.06 (s, 2H), 5.40 (s, 2H), 6.35 (d, J=1.8 Hz, 1H), 6.37 (d, J=7.8 Hz, 1H), 6.74 (d, J=1.8 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:21])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(N(CCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(p-anisidino)butyric acid and ethyl glycinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(p-anisidino)butyryl]glycinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(p-anisidino)butyryl]glycine (viscous oil).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH2:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:12][CH:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[CH:19]4)[CH2:40][CH2:39]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4ncccc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(CC3CCN(CC4COc5ccc6ncccc6c5O4)CC3)c2c1
Temperature: 77.5 °C

Procedure:
(2R)-2,3-Dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.46 g, 1.24 mmole) and 5-fluoro-3-(4-piperidinylmethyl)-1H-indole (1.00 g, 4.32 mmole) were combined in 40 mL of DMSO and heated at 75-80° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated sodium bicarbonate solution. The organic phase was removed, washed with saturated brine, dried over magnesium sulfate and concentrated to an oil in vacuum. This was column chromatographed on silica gel using first methylene chloride to elute impurities and then 3% methanol in methylene chloride to elute 0.200 g of the product as a yellow oil. The oil was crystallized from isopropanol with the addition of 0.040 g of oxalic acid to give 0.107 g of the (S)-enantiomer of the title compound as a light red solid (m.p. 184° C.), which contained both water and isopropanol.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:11]=[CH:10][S:9][CH:8]=1>C(Cl)Cl>[Br:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccsc1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1sccc1Br
Reaction time: 1 h
Yield: 30.6 %

Procedure:
Chlorosulfonic acid (20 ml, 300 mmol) was added to a solution of 3-bromothiophene (8.15 g, 50 mmol) in methylene chloride (50 ml) at −78° C. over a 20 min. period. After the completion of addition, the cold bath was removed and stirring continued at ambient temperature for 1 hr. The reaction mixture was carefully added, dropwise, to crushed ice (100 g). The mixture was extracted with methylene chloride (2×100 ml). The combined organic layers was dried over MgSO4 and evaporated. The crude product was purified by flash chromatography on silica gel using hexane as the eluent resulting in 3-bromothiophene-2-sulfonyl chloride (4 g, 30% yield) and 4-bromothiophene-2-sulfonyl chloride (200 mg, ≦1%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:24]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:12])(=[O:10])=[O:9])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: O=S(=O)(Cc1ccccc1)c1ccc(Br)cc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A solution of 4-bromo-2-chlorobenzenesulfonyl chloride (1.16 g), sodium sulfite (1.01 g) and sodium bicarbonate (672 mg) in water (8 mL) was stirred at 100° C. for 1.5 hours. The reaction solution was cooled to 50° C. and tetrabutylammonium bromide (1.29 g) and benzyl bromide (1.43 mL) were added, after which the mixture was stirred at 70° C. for further three hours. The reaction solution was cooled to room temperature and water was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound as a white solid (1.29 g, 94%).