Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:5][C:6](=[O:26])[C@:7]([NH2:25])([CH2:21][C:22](=[O:24])[OH:23])[N:8]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])C(OC(C)(C)C)=O.C(OCC)C.[ClH:40].O1CCOCC1>>[ClH:40].[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:5][C:6](=[O:26])[C@:7]([NH2:25])([CH2:21][C:22](=[O:23])[OH:24])[NH:8][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@](N)(CC(=O)O)N(C(=O)OC(C)(C)C)C(=O)C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C
Reaction time: 1 h

Procedure:
N-t-Butoxycarbonyl-α-aminoisobutyryl-α-L-aspartyl-L-phenylalanine methyl ester (2.3 g) was dissolved under ice cooling in 4N-HCl/dioxane (20 ml), and the mixture was stirred for one hour. Ethyl ether (150 ml) was added, and the crystals which separated out were collected by filtration. Yield: 1.8 g.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[CH2:9][C@H:8]([N:10]([C:15]([C:17]2[N:18]=[N:19][N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:21]=2[CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)[CH3:3]>Cl.CO>[OH:1][CH:2]([C@H:4]1[CH2:5][NH:6][CH2:7][C@@H:8]([N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:15]([C:17]2[N:18]=[N:19][N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:21]=2[CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[O:16])[CH2:9]1)[CH3:3]
Reactant: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Agent: Cl
Solvent: CO
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(C)O)C2)nnn1-c1ccccc1C
Temperature: 25 °C
Reaction time: 13 h
Yield: 96.5 %

Procedure:
tert-Butyl (3R,5S)-3-(1-hydroxyethyl)-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (319 mg) was dissolved in 10% hydrogen chloride-methanol (4 ml), and the mixture was stirred at room temperature for 13 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residual aqueous layer was neutralized with 3.5M aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue and fumaric acid (27.9 mg) were dissolved in methanol (2 ml), and the solvent was evaporated under reduced pressure to give the object product (254 mg).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([C:16]3[C:17](=O)[NH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:5]=2[N:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:5]=2[N:6]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nc2c(o1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=O
Solvent: C1COCCO1
Product: Cc1nc2c(o1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
A mixture of the product from step (iii), (0.075 g) and Lawesson's reagent (0.094 g) in 1,4-dioxane (5 ml) under nitrogen was heated at reflux 16 h. The reaction mixture was partitioned between ethyl acetate and saturated brine. The organic phase was collected, dried over magnesium sulphate and solvent evaporated under reduced pressure. Purification was by flash chromatogaphy eluting with 0 to 2% ethanol in dichloromethane followed by a second column eluting with 40% ethyl acetate in toluene to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH:3]=[CH2:4].[CH:18](=[O:22])/C=C/C>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[N:5]([C:1](=[CH:2][CH2:3][CH3:4])[CH:18]=[O:22])[CH2:14][CH2:13]2
Reactant: C=CCCN1CCc2cc(OC)ccc2C1=O
Reactant: C/C=C/C=O
Product: CCC=C(C=O)N1CCc2cc(OC)ccc2C1=O

Procedure:
The title compound 50 is prepared according to the procedure reported in step C of Example 8 with amide 49 (230.0 mg, 0.99 mmol) and crotonaldehyde (3.98 mmol, 4 equiv) as reactants. Yellow solid. (Yield 0.147 g, 57%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[N:7][CH:8]=1.[H][H]>C(OCC)(=O)C.[Pd]>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[N:7][CH:8]=1
Reactant: [H][H]
Reactant: O=C1CCCC1=Cc1ccc(C(F)(F)F)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCCC1Cc1ccc(C(F)(F)F)cn1

Procedure:
A solution of 2-{[5-(trifluoromethyl)pyridin-2-yl]methylidene}cyclopentan-1-one (0.513 g, 2.13 mmol) in ethyl acetate (20 ml) was added palladium on carbon (10% wt, 50% wet, 0.226 g, 0.11 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-40% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7](=[O:27])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:26])[C:16]([C:18]2[CH:23]=[C:22](Cl)[N:21]=[N:20][C:19]=2[Cl:25])=[O:17])[N:13]=1.[OH-].[K+].[C:33](=O)(O)[O-:34].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7](=[O:27])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:26])[C:16]([C:18]2[CH:23]=[C:22]([O:34][CH3:33])[N:21]=[N:20][C:19]=2[Cl:25])=[O:17])[N:13]=1
Reactant: CN(Cc1csc(NC(=O)NCc2cccc(F)c2)n1)C(=O)c1cc(Cl)nnc1Cl
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N(C)Cc2csc(NC(=O)NCc3cccc(F)c3)n2)c(Cl)nn1

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid {2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide (47 mg) was treated with potassium hydroxide (56 mg) in MeOH (5 mL) over night. The resultant mixture was diluted with water (10 mL) and the pH was adjusted to 9-10 by sodium bicarbonate. After evaporation of MeOH, the resultant precipitate-3-chloro-6-methoxypyridazine-4-carboxylic acid {2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide was collected, briefly rinsed with water and dried. The desired product was confirmed by 1HNMR and LC-MS.
Reaction SMILES: [C:1]1([CH:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.[C:30]1(O)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>>[C:38]1([O:10][CH2:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:11])[C:39]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: OCCC(O)c1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: O[C@H](CCOc1cccc2ccccc12)c1ccccc1
Yield: 87 %

Procedure:
Using (R) 3-phenyl-1,3-dihydroxypropane, 1.05 equivalents of 4-toluenesulfonyl chloride, 0.05 equivalents of poly-DMAP™, and 2.0 equivalents of triethylamine, 1.0 equivalents of 1-naphthol, and 1.1 equivalents of 50% sodium hydroxide as in example I.C.1, an 87% yield of (R)-(-)-3-(1-naphthalenyloxy)-1-phenyl-1-propanol was obtained. (HPLC chiral purity, 98.6% ee)
Reaction SMILES: O[CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17](C)[N:16]=1>C1(C)C=CC=CC=1>[CH2:5]([O:4][P:3]([CH2:2][C:17]1[CH:18]=[C:19]([CH3:21])[CH:20]=[C:15]([CH3:14])[N:16]=1)([O:7][CH2:8][CH3:9])=[O:10])[CH3:6]
Reactant: CCOP(=O)(CO)OCC
Reactant: Cc1cc(C)nc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc(C)cc(C)n1)OCC

Procedure:
A solution of diethyl hydroxymethylphosphonate (1 mmole) in toluene was treated with sodium hydride (1.1 mmole) at 0° C., and after 15 min 2-bromomethyl-4,6-dimethylpyridine (1 mmole) was added. After 3 h the reaction mixture was subjected to extraction and chromatography to give 2-diethylphosphonomethyl-4,6-dimethylpyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[C:33]([CH3:39])=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)[C:17]=2[O:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[C:33]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(O)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccsc3)c3ccccc23)CC1
Product: Cc1c(F)cccc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1-c1ccsc1

Procedure:
From the compound of step 3 (50 mg, 112 μmol), the title compound was prepared analogously as described in example 1, step 2, using 3-fluoro-2-methylphenol. Yield: 11 mg.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[CH2:10]([C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[O:1][CH:20]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22])[CH2:11][CH3:12]
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: CCCc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(C#N)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4.50 g (27.95 mmol) of the product of Step B in 30 mL of acetone was added 4.64 g (33.54 mmol) of powdered potassium carbonate and the reaction mixture was stirred for 10 minutes. Methyl α-bromo-3,4-methylenedioxyphenylacetate (8.01 g; 29.35 mmol) was then added and the reaction mixture refluxed overnight. The reaction mixture was cooled, filtered, and the filtrate evaporated in vacuo, dried in a vacuum to afford 10.30 g (9.87 g theoretical) of the title compound which was used without purification in the next step.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9]>C(O)(=O)C.O>[Br:1][C:11]1[CH:12]=[C:13]([CH3:14])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c(Br)cc1C
Temperature: 60 °C

Procedure:
Br2 (1.11 mL, 21.7 mmol) was added to a rt suspension of 3-methoxy-4-methylbenzoic acid (3.00 g, 18.1 mmol) in a mixture of acetic acid (23 mL) and water (23 mL) and the mixture was heated to 60° C. for 2 h. The mixture was allowed to reach rt and the solids were filtered and rinsed with water to yield 2-bromo-5-methoxy-4-methylbenzoic acid as a white solid which was used as such in the next step. LC-MS A: tR=0.76 min, no ionization.
Reaction SMILES: [N:1](=[C:3]([C:9]#[N:10])[C:4](OCC)=[O:5])[OH:2].[Na].[Cl:12][C:13]1[C:14]([O:23][CH3:24])=[C:15]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:16]([NH2:18])=[NH:17].O>CO.C(O)(=O)C>[NH2:10][C:9]1[N:17]=[C:16]([C:15]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:13]([Cl:12])[C:14]=2[O:23][CH3:24])[NH:18][C:4](=[O:5])[C:3]=1[N:1]=[O:2]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: COc1c(Cl)cc(Cl)cc1C(=N)N
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(Cl)cc(Cl)cc1-c1nc(N)c(N=O)c(=O)[nH]1
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Ethyl α-oximinocyanoacetate (21 g.) was added to a solution of sodium (11.3 g.) in anhydrous methanol (300 ml.). Crude 3,5-dichloro-2-methoxybenzamidine (24 g.) dissolved in a little anhydrous methanol was added, and the mixture was heated to reflux with stirring for 8 hours. The mixture was poured into water (2000 ml.) and acidified with glacial acetic acid. The solid obtained was filtered off, washed with water and recrystallised from glacial acetic acid to give 4-amino-2-(3,5-dichloro-2-methoxyphenyl)-5-nitrosopyrimid-6-one (6.8 g.), m.p. 265° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:41][C:42]([F:53])([F:52])[C:43]1[CH:44]=[C:45]([N:49]=[C:50]=[O:51])[CH:46]=[CH:47][CH:48]=1>>[F:41][C:42]([F:52])([F:53])[C:43]1[CH:44]=[C:45]([NH:49][C:50]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)=[O:51])[CH:46]=[CH:47][CH:48]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccc(C(F)(F)F)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (54 mg) and 3-trifluoromethyl-phenyl isocyanate (56.1 μl) instead of ethyl isocyanate, in the same manner as in Example 1-D-03, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-trifluoromethyl-phenyl)-amide was obtained, and then the PMB groups were removed according to Deprotection method 1′, to obtain the desired compound (D-47) as a colorless solid (8.2 mg, 17%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.O=[CH:11][CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1.C(O)C.II>COCCOC.C(O)(=O)C>[CH3:9][N:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[N:1]=[C:11]1[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:27][CH:28]=1
Reactant: CNc1ncccc1N
Reactant: O=CCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: II
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: CCO
Product: Cn1c(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc2cccnc21
Yield: 3 %

Procedure:
A procedure similar to that described in Example 18 was repeated, except that 0.94 g of 3-amino-2-methylaminopyridine (prepared as described in Preparation 105), 2.10 g of 5-[4-(3-oxopropoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 107), 6 ml of ethanol, 3 ml of acetic acid, 2.32 g of iodine and 30 ml of 1,2-dimethoxyethane were used. After working up the product as described in Example 18, the resulting crude product was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 85 mg of the title compound, melting at 96°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[C:21]([O:23]C)=[O:22])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CO.O1CCOCC1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[C:21]([OH:23])=[O:22])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)C1Cc2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2c3ccccc3CC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 1-(4-methoxyphenylsulfonyl)indoline-2-carboxylate (47.1 g, 135.6 mmol) was dissolved in a mixture of methanol/dioxane/4 M NaOH (15/4/1,1020 ml, 203.4 mmol NaOH, 1.5 eq.), and further 4 M NaOH (153 ml, 610.2 mmol, 4.5 eq.) was added thereto. The solution was stirred overnight at room temperature and then concentrated using a rotary evaporator. Ethyl acetate was added to the residue, and the mixture was washed with 0.5 M KHSO4. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with saturated NaCl solution, dried (sodium sulfate) and concentrated in vacuo. The residue was washed with diethyl ether, filtered and dried.
Reaction SMILES: CC1(C)COC2(CCC(CCN[C@H](C3C=CC4C(=CC=CC=4)C=3)C)(O)CC2)OC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CC1(C)CO[C:46]2([CH2:69][CH2:68][C:49]3([O:54][C:53](=[O:55])[N:52]([C@H:56]([C:58]4[CH:67]=[CH:66][C:65]5[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=5)[CH:59]=4)[CH3:57])[CH2:51][CH2:50]3)[CH2:48][CH2:47]2)[O:45]C1>>[CH:59]1[C:60]2[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:66]=[CH:67][C:58]=1[C@@H:56]([N:52]1[CH2:51][CH2:50][C:49]2([CH2:68][CH2:69][C:46](=[O:45])[CH2:47][CH2:48]2)[O:54][C:53]1=[O:55])[CH3:57]
Reactant: C[C@@H](c1ccc2ccccc2c1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc2ccccc2c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc2ccccc2c1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 3,3-dimethyl-9-{2-[(S)-1-naphthalen-2-yl-ethylamino]-ethyl}-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 12,12-dimethyl-3-[(S)-1-naphthalen-2-yl-ethyl]-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained thereafter is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 56% of theory; LC (method 6): tR=1.34 min; Mass spectrum (ESI+): m/z=338 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[OH:15][CH:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][OH:27])[CH:20]=1)[CH2:17][NH2:18]>C(O)C.[Pd].C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:18][CH2:17][CH:16]([OH:15])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][OH:27])[CH:20]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1
Reaction time: 18 h
Yield: 43 %

Procedure:
A solution of 1-(4-carbomethoxyphenyl)propan-2-one (70 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine (66.7 g) in ethanol (1750 cm3) was stirred under reflux for 4 hours. The solution was cooled and added to a suspension of 10% palladium on charcoal, (Johnson Matthey type 87L), (20 g) in ethanol (50 cm3) and the resulting mixture hydrogenated at 90 psi and 50°-55° for 18 hours. The mixture was filtered through a Claraid bed, the residue washed with ethanol (about 500 cm3) and the filtrate evaporated under reduced pressure to yield a viscous gum. The gum was dissolved in hot ethyl acetate (100 cm3) and decanted from a small amount of residual brown oil. On standing a white solid crystallised which was filtered off, washed with diethyl ether (about 100 cm3) and dried to give the title compound 56.3 g (43%), mp 139°-141°. (13C NMR: indicated this to be a 7:3 mixture of diastereoisomers). On standing two further crops of the title compound crystallised from the filtrate giving a total yield of 84.7 g (64.7%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](B(O)O)[CH:36]=2)[CH:31]=[CH:30]1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:36]=[C:37]2[C:32]([CH:31]=[CH:30][NH:29]2)=[CH:33][CH:34]=1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Yield: 10.5 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with (1H-indol-6-yl)boronic acid (23 mg, 0.14 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.43 mol) according to the method described in Example 3 to give 7 mg (14% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.Cl.[OH-].[Na+]>CC(O)C.O>[NH2:9][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Nc1cnc(Cl)c(Cl)c1

Procedure:
A solution of 2,3dichloro-5-nitropyridine (prepared as described in Rocz. Chem. (1968), 42 (12), 2079–2088; CAN 70:106327; 2.83 g) in propan-2-ol (40 ml) was added over 10 minutes to a stirred mixture of reduced iron powder (2.96 g), propan-2-ol (25 ml), water (15 ml) and concentrated hydrochloric acid (0.24 ml) at 70° C. The mixture was heated to reflux for 1 hour then sodium hydroxide (0.13 g) in water (1 ml) was added and the reaction filtered whilst hot through kieselguhr. The insoluble material was washed with ethyl acetate and water and the filtrates were combined and evaporated under reduced pressure to a small volume. The residue was extracted with dichloromethane (three times) and the extracts were combined, washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give the required product, 2.11 g, as a pale yellow solid, m.p. 117–119° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([NH:5][CH2:6][CH2:7][O:8][CH2:9][C:10]#[C:11][C:12]1[C:13](=[O:27])[NH:14][C:15](=[O:26])[N:16]([CH:25]=1)[C@@H:17]1[O:24][C@H:21]([CH2:22][OH:23])[C@@H:19]([OH:20])[CH2:18]1)=[O:4].C([O-])=O.[NH4+]>CO.[Pd]>[F:28][C:2]([F:1])([F:29])[C:3]([NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:27])[NH:14][C:15](=[O:26])[N:16]([CH:25]=1)[C@@H:17]1[O:24][C@H:21]([CH2:22][OH:23])[C@@H:19]([OH:20])[CH2:18]1)=[O:4]
Reactant: O=C(NCCOCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(NCCOCCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Yield: 87 %

Procedure:
A solution of 5-[3-(2-trifluoroacetamidoethoxy)propynyl]-2'-deoxyuridine (3.4 g, 8.1 mmol) in methanol (20 ml) is stirred with ammonium formate (prepared by addition of 3 ml, 79 mmol of cold 98% formic acid into 2 ml, 50 mmol of dry ice frozen 25% ammonia) and 0.2 g of 10% Pd/C for 7 hours at room temperature under hydrogen atmosphere. The catalyst is removed by filtration, the filtrate evaporated and product is purified on LiChroprep RP-18 column by the above procedure. Fractions containing the desired product are combined and evaporated to dryness in vacuo and the resultant solid is triturated with dry ether to give 3.0 g (87% product, m.p. 107-110°; max in nm, in 0.1M triethylamine-acetate (pH 7.5), 220, 268. Analysis calculated for C16H22F3N3O7 : C, 45.18; H, 5.21; N, 9.88; F, 13.40. Found C, 45.16; H, 5.16; N, 9.68; F, 13.13.