Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH2:9][C:8]([C:23]#[N:24])([C:10]2[CH:15]=[CH:14][C:13](OC)=[C:12]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:11]=2)[CH2:7][CH2:6][C:5]=1[O:25][CH2:26][O:27][CH3:28])([OH:3])=O.C[N:30]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>COCCOC>[NH2:30][C:1]([C:4]1[CH2:9][C:8]([C:23]#[N:24])([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22]3)[CH:11]=2)[CH2:7][CH2:6][C:5]=1[O:25][CH2:26][O:27][CH3:28])=[O:3]
Reactant: COCOC1=C(C(=O)O)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Product: COCOC1=C(C(N)=O)CC(C#N)(c2cccc(OCC3CC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
A mixture of 2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene (0.26 g. 0.67 mmol), N-methyl morpholine (0.09 ml, 0.8 mmol) and isobutyl chloroformate (0.1 mL, 0.77 mmol) in dry 1,2-dimethoxyethane (7 mL) was stirred under an argon atmosphere at room temperature for 10 min. Ammonium hydroxide (0.07 mL, 1.0 mmol) was added and stirring was continued for 0.5 h. The mixture was partitioned between methylene chloride and 5% aqueous sodium carbonate, was extracted three times, the organic layer was dried (potassium carbonate) and the solvent was removed in vacuo to provide a white solid (0.22 g, 85%): m.p. 120°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:17]=[CH2:18])[CH:13]=2)[N:8]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12](/[CH:17]=[CH:18]/[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:13]=2)[N:8]=1
Reactant: Brc1cccnc1
Reactant: C=Cc1ccc2nc(NCc3ccccc3OC)ccc2c1
Product: COc1ccccc1CNc1ccc2cc(/C=C/c3cccnc3)ccc2n1

Procedure:
(2-Methoxy-benzyl)-(6-vinyl-quinolin-2-yl)-amine (240 mg, 0.828 mmol) was reacted with 3-bromopyridine (170 mg, 1.08 mmol) as described in example 2 step B. The title compound was obtained as a yellow waxy solid (100 mg, 33%), MS: m/e=368.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([Cl:24])[CH:7]=[C:8]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:9]=2[CH2:11]O)[NH:4][N:3]=1.S(Cl)(Cl)=O.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>C(#N)C>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:29]([CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:15](=[O:17])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:8]=3[CH:7]=[C:6]([Cl:24])[C:5]=2[NH:4][N:3]=1
Reactant: NCCN1CCCCC1
Reactant: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]nc(Cl)c2c1CO)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
(S)-Dimethyl 2-((3,7-dichloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (990 mg, 2.64 mmol) was dissolved in thionyl chloride (2.0 M in dichloromethane) (20 mL, 40.0 mmol). Mixture stirred at room temperature for 3 hours. Mixture was concentrated by roto-vap. Residue was dissolved in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate. Organics were dried MgSO4, filtered and then concentrated to dryness. A portion of the residue (460 mg, 1.169 mmol) was dissolved in acetonitrile (15 mL). 1-(2-Aminoethyl)-piperidine (600 μl, 4.21 mmol) was added to the mixture followed by potassium carbonate (200 mg, 1.447 mmol). Mixture was warmed to reflux and held with stirring for 1 hour. Mixture was cooled to room temperature and then filtered over celite. Filtrate was concentrated by roto-vap. Residue was dissolved in toluene (15 mL). Acetic acid (1.0 mL, 17.47 mmol) was added to the mixture. Reaction was warmed to reflux and held with stirring for 16 hours. Mixture was cooled to room temperature and then concentrated by roto-vap. Residue was suspended in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting 2M ammonia in methanol-dichloromethane afforded the title compound as amber oil in 51% yield. (M+H)+=453.0, 455.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([OH:20])=O)[CH3:2].O=S(Cl)[Cl:23]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([Cl:23])=[O:20])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Yield: 89.9 %

Procedure:
A solution of Example B1 (35 g, 126 mmol) in toluene (400 mL) was treated with SOCl2 (120 g, 1.01 mol) and one drop of DMF, and was heated to reflux for 2 h. The mixture was concentrated in vacuo to afford 4-ethoxy-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl chloride (33.5 g, 100% yield). The residue was carried into the next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH:20][NH2:21])=O.CO[CH:24](OC)[N:25]([CH3:27])C.C(O)(=O)C.N[C:35]1[CH:40]=[CH:39]C=[CH:37][CH:36]=1>C(#N)C>[C:24]1([N:25]2[CH:27]=[N:21][N:20]=[C:18]2[C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:4]=2)[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ccccc1
Reactant: NNC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Solvent: CC(=O)O
Solvent: CC#N
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1nncn1-c1ccccc1
Temperature: 125 °C
Yield: 54.2 %

Procedure:
A solution of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carbohydrazide (0.2 g, 0.67 mmol) and N,N-dimethylformamide dimethylacetal (0.09 mL, 0.67 mmol) in acetonitrile (2 mL) was heated at 55° C. for 45 min. After that time, acetic acid (2 mL) and aniline (0.06 mL, 0.66 mmol) were added and the temperature was increased to 125° C. for an additional 2 h. During this time, the acetonitrile was allowed to distill-off. The reaction was then concentrated to a dark residue and the crude product purified by column chromatography (silica gel, ethyl acetate to 4:1 ethyl acetate/methanol) to give 3-(4-phenyl-4H-1,2,4-triazol-3-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.137 g, 53%) as a light yellow oil that crystallized upon standing.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[CH:32]=[O:33]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[C:24]([CH:32]=[O:33])[CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: O=Cc1cc(B(O)O)ccc1F
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(F)c(C=O)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-fluoro-3-formylphenylboronic acid (143 mg, 0.85 mmol) the subtitle compound was obtained (146 mg, 44%). MS 393 m/z (M+H)+.
Reaction SMILES: C(C1C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC(CC)=CN=1)C.Br[C:23]1[C:28]([CH3:29])=[N:27][C:26]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])=[C:25]([CH3:38])[N:24]=1.[C:39]1([NH2:49])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][N:40]=1>>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[C:26]1[N:27]=[C:28]([CH3:29])[C:23]([NH:49][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[CH:41][N:40]=2)=[N:24][C:25]=1[CH3:38]
Reactant: Nc1nccc2ccccc12
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1Br
Agent: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1Nc1nccc2ccccc12

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 2-bromo-5-(2,4-dichlorophenyl)-3,6-dimethylpyrazine and isoquinolin-1-amine, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 2.36, 2.93, 6.75, 7.38, 7.53, 7.57, 8.96; HRMS (ESI+) calcd for C21H16Cl2N4 (M+H)+ 395.0830, found 395.0821.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:4].[C:18]([O:22][C:23](=[O:28])[NH:24][CH2:25][CH:26]=O)([CH3:21])([CH3:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:18]([O:22][C:23](=[O:28])[NH:24][CH2:25][CH2:26][NH:1][C@H:2]([C:3](=[O:4])[NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: N[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Temperature: 50 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
A solution of compound 12B (2.03 g, 8 mmol), (2-oxo-ethyl)-carbamic acid tert-butyl ester (1.27 g, 8 mmol) and NaBH(OAc)3 (1.70 g, 8 mmol) in DCM (30 ml) was maintained at ambient temperature overnight followed by the addition of NaBH(OAc)3 (3.39 g, 16 mmol). Reaction mixture was stirred at 50° C. for 3 hours, diluted with EtOAc (200 ml) and extracted with water (200 ml), 5% aq. bicarbonate (200 ml) and brine (200 ml). Organic layer was dried over anh. MgSO4 and evaporated in vacuum. Residue was dissolved in DMSO (5 ml) and subjected to HPLC purification. [Phenomenex Gemini C-18 column, 110 Å (30×100 mm); flow rate=45 ml/min; mobile phase A: 100% water, 0.1% TFA; mobile phase B: 100% ACN, 0.1% TFA; gradient elution from 25% B to 70% B in 70 min., detection 254 nm]. Fractions containing the desired product were combined and neutralized with 1 M NaOH. ACN was evaporated. Residual solution was extracted with EtOAc (2×100 ml). Organic layer was dried over anh. MgSO4 and evaporated in vacuum to provide target product (1.10 g, 35%) as light yellow oil. LC-MS [M+H] 397.2 (C19H32N4O3S+H, requires 397.56).
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH:23](O)[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]1([S:7]([CH:23]2[O:22][CH:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:28][CH:27]=3)[CH2:25][CH2:24]2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCC(COc2ccc(F)cc2)O1
Reactant: O=S(=O)(O)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCC(COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To benzenesulfonic acid sodium salt (10.0 g, 0.061 mol), 25% HCl was added dropwise with stirring until the solid dissolved. The reaction mixture was extracted (100 mL each, 3 times) with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfonic acid (7.8 g, 90%). To a 100 mL round bottom with a magnetic stir bar, benzenesulfonic acid (4.61 g, 0.0324 mol), CaCl2(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL) were added. The reaction mixture was cooled to 0° C. and (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydrofuran (4.6 g, 0.0216 mol) in dry CH2Cl2 (20 mL) was added. The reaction mixture was stirred for 3 h and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.25). The reaction mixture was filtered through celite and washed with CH2Cl2 (3 times). The combined organic layer was washed with saturated aqueous Na2CO3, water brine and dried over Na2SO4. Solvent was removed under reduced pressure to afford the crude (2S) (5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 14 which was crystallized from chloroform-hexane to give pure white solid, yield 6.8 g (93%), m.p. 102° C.-104° C. 1H NMR (200 MHz, CDCl3): δ 1.90-3.0 (m, 4 H), 3.85-5.0 (m, 4 H), 6.70-7.05 (m, 4 H), 7.45-7.72 (m, 3 H), 7.77-8.0 (m, 2 H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:12]([CH3:26])[CH:11]=1)[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:26][C:12]1[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:15]=[CH:14][C:13]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=1
Reactant: Cc1cc([C@H](C)NC(=O)OC(C)(C)C)ncc1-c1ccnc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc([C@H](C)N)ncc1-c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of (S)-tert-butyl(1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)carbamate (200 mg, 0.524 mmol) in DCM (2 ml) at −78° C. was added trifluoroacetic acid (2 mL, 12.98 mmol). The solution was stirred at r.t. for 1 hr. The mixture was concentrated, diluted with 10 mL DCM and stirred with solid MP-carbonate to remove TFA. Filtered and concentrated to give 147 mg (S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine as a light brown sticky oil. MS m/z 282.1 (M+H). Rt=0.85 min. (Column: XBridge C18 3.5 um 2.1×50 mm. Solvent A: 2% Acetonitrile, 3.75 mM Ammonium Acetate, Water. Solvent B: Acetonitrile. Gradient: 5-95% B over 1.70 min. Flow rate: 2 mL/min.) The crude product was used to next step without further purification.
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:42]([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:42]([C:36]3[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=3)([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)[OH:43])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: COc1ccc(C(=O)c2cccnc2)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2cccnc2)c2ccc3nc(OC)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.05 mL, 0.125 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (32.9 mg, 0.135 mmol, Intermediate 16) in dry THF (2 mL) in a dry ice-acetone bath. After 5 minutes, a solution of (3,4-dimethoxyphenyl)(pyridin-3-yl)methanone (32.9 mg, 0.135 mmol, Intermediate 27: step b) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 10 minutes, the mixture was warmed to room temperature and the reaction was quenched with saturated ammonium chloride. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 20-100% EtOAc-Hexanes) to provide the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.61 (d, J=1.8 Hz, 1H), 8.53 (dd, J=4.8, 1.6 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.69 (dt, J=8.0, 2.0 Hz, 2H), 7.57-7.52 (m, 3H), 7.35 (d, J=8.6 Hz, 2H), 7.29-7.25 (m, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 6.66 (dd, J=8.4, 2.2 Hz, 1H), 6.44-6.42 (m, 1H), 4.31 (s, 2H), 4.08 (s, 3H), 3.88 (s, 3H), 3.76 (s, 3H); MS m/e 593.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([OH:27])=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1.Cl.[NH2:29][C@@H:30]([C:35]([NH2:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33]>>[NH2:37][C:35]([C@H:30]([NH:29][C:25]([C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)=[O:27])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:36]
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Agent: Cl
Product: CC(C)C[C@@H](NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1)C(N)=O

Procedure:
The title compound was prepared from the product of example 148 step (i) (0.15 g) and (R)-leucinamide hydrochloride (0.07 g) according to the method of example 115, step (i). Yield 0.05 g as a solid.
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-:33].[Na+:34].[CH:35]1[C:40]([CH2:41][CH2:42][C:43]2[C:47]3[C:48]([NH:50][C:51]([NH2:53])=[N:52][C:46]=3[NH:45][CH:44]=2)=[O:49])=[CH:39][CH:38]=[C:37]([C:54]([NH:56][C@@H:57]([C:63]([O-:65])=[O:64])[CH2:58][CH2:59][C:60]([O-:62])=[O:61])=[O:55])[CH:36]=1.[Na+].[Na+]>>[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].[CH:39]1[C:40]([CH2:41][CH2:42][C:43]2[C:47]3[C:48]([N:50]=[C:51]([NH2:53])[NH:52][C:46]=3[NH:45][CH:44]=2)=[O:49])=[CH:35][CH:36]=[C:37]([C:54]([NH:56][C@H:57]([C:63]([O-:65])=[O:64])[CH2:58][CH2:59][C:60]([O-:62])=[O:61])=[O:55])[CH:38]=1.[OH2:33].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[Na+:34].[Na+:34]
Reactant: [OH-]
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)O)C(=O)O)cc3)c2c(=O)[nH]1
Agent: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)[O-])C(=O)[O-])cc3)c2c(=O)[nH]1
Agent: [Na+]
Agent: [Na]
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1
Product: O

Procedure:
Surprisingly we found that the crucial feature of all successful transformations to Pemetrexed Disodium Form IV is the presence of Pemetrexed Monosodium during the transformation. Routes starting from pure Pemetrexed Disodium Heptahydrate, Pemetrexed Disodium 2.5 hydrate or Pemetrexed Disodium Form A in the presence of seeding crystals of Pemetrexed Disodium Form IV were not successful and resulted in isolation of Pemetrexed Disodium Form A. The same transformations, if carried out in the presence of 0.15 eq of Pemetrexed Monosodium were successful and after addition of 0.15 eq NaOH allowed the isolation of pure Pemetrexed Disodium Form IV. The use of 0.15 eq HCl instead of 0.15 eq Pemetrexed Monosodium under the same conditions resulted in isolation of Pemetrexed Disodium Form A without any Pemetrexed Disodium Form IV. Transformations via isolated Pemetrexed Monosodium gave complete transformation to Pemetrexed Disodium Form IV if either 1.0 eq NaOH were added slowly (over a period of several hours) to Pemetrexed Monosodium or if initially only 0.85 eq of NaOH (based on Pemetrexed Monosodium) were added, followed by 0.15 eq once the transformation to Pemetrexed Disodium Form IV was complete. Very fast addition (<1 min) of 1.0 eq NaOH resulted in formation of Pemetrexed Disodium Form A containing traces of Pemetrexed Disodium Heptahydrate.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.C([O:23][C@@H:24]1[C@H:28]([O:29]C(=O)C2C=CC=CC=2)[C@@H:27]([CH2:38][O:39]C(=O)C2C=CC=CC=2)[O:26][C@H:25]1[N:48]1[CH:56]=[N:55][C:54]2[C:49]1=[N:50][C:51]([Cl:58])=[N:52][C:53]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:58][C:51]1[N:52]=[C:53]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:3]2)[C:54]2[N:55]=[CH:56][N:48]([C:49]=2[N:50]=1)[C@@H:25]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:24]1[OH:23].[O:8]([CH:4]1[CH2:5][CH2:6][CH2:7][NH:2][CH2:3]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CCCC(Oc2ccccc2)C1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCC(Oc5ccccc5)C4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: c1ccc(OC2CCCNC2)cc1
Yield: 215.7 %

Procedure:
2-Chloro-N-(3-phenoxy-1-piperidinyl)adenosine was prepared according to method A as described in Example 6 by reacting 1-amino-3-phenoxypiperidine (0.60 g, 3.4 mmol) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the desired compound (0.65 g, 43%) (after column chromatography) as a foam, 1H NMR (DMSO-d6) δ 3.53-3.60 (1H, m, H-5'a), 3.64-3.72 (1H, m, H-5'b), 3.96 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.50-4.59 (1H, m, H-2' and --C--H) ), 5.07 (1H, t, 5'-0H), 5.23, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 6.79-7.32 (5H, 3m, Ar--H), 8.45 (1H, s, H-8), 9.55 (1H, s, N--H).
Reaction SMILES: O[CH:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[S:20]1C=CC=C1CC(O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC([O:52][CH:53]([CH3:55])C)=O>O1CCCC1>[C:53]([S:20][CH:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1)(=[O:52])[CH3:55]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: OC1CCC2(CC1)CCC(CCc1ccoc1)CC2
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CCC2(CCC(CCc3ccoc3)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.200 g of 9-hydroxy-3-(2-(3-furyl)ethyl)-spiro[5.5]-undecane (I-ap, Ex. 38) and 0.11 ml of thiolacetic acid in 9 ml of anhydrous tetrahydrofuran was added to a solution of 0.40 g of triphenylphosphine and 0.30 ml of diisopropyl azodicarboxylate in 1 ml of anhydrous tetrahydrofuran, and the mixture stirred at 0° C. under argon atmosphere for 2 hrs. Silica gel was then added, the mixture was evaporated to dryness and the residue purified by chromatography (SiO2 ; n-hexane/diethylether 90/10) to give 0.120 g of 9-acetylthio-3-(2(3-furyl)ethyl)-spiro[5.5]undecane as a light oil. TLC: Rf=0.72 (SiO2 plates, n-hexane/diethylether 90/10). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 7.40 (1H, m), 7.21 (1H, m), 6.25 (1H, m), 3.48 (1H, m), 2.48 (2H, t), 2.30 (3H, s), 1.90-0.85 (19H, m).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1CCCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCCN(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of tert-butyl methyl(piperidin-3-yl)carbamate (1.00 g, 4.67 mmol) in THF (25 mL) was added triethylamine (0.70 mL, 5.0 mmol) and 2-chloro-5-nitropyridine (500 mg, 3.1 mmol). The reaction mixture was then stirred at room temperature for 16 h, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, ethyl acetate/hexanes) afforded the desired product (1.03 g, 99%) as a yellow solid. ESI MS m/z 337 [C16H24N4O4+H]+