Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O.Cl.[NH2:24][C:25]([NH2:27])=[NH:26]>C(O)C>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)[N:26]=[C:25]([NH2:27])[N:24]=1
Reactant: O=C(Cc1ccncc1)c1ccco1
Reactant: N=C(N)N
Reactant: O=Cc1ccco1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(-c2ccco2)c(-c2ccncc2)c(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
After dissolving sodium (540 mg, 23.5 mmol) in anhydrous ethanol (200 ml), 1-(2-furyl)-2-(4-pyridyl)-1-ethanone (2.00 g, 10.7 mmol) and 2-furaldehyde (0.97 ml, 11.7 mmol) were successively added thereto and the mixture was stirred at room temperature. After 1.5 hours, guanidine hydrochloride (7.0 g, 73.3 mmol) was added thereto, followed by heating under reflux for 14 hours. After cooling as it was, the reaction mixture was concentrated and the residue was suspended in tetrahydrofuran. Then, the insoluble matters were filtered off and washed with tetrahydrofuran, and the solvent of the filtrate was evaporated. To the residue were added tetrahydrofuran (80 ml) and active manganese dioxide (30.0 g), followed by heating under reflux for 2 hours. After cooling as it was, the manganese dioxide was filtered off through Celite and washed with tetrahydrofuran. The combined filtrates were concentrated, and then methanol was added to the residue. The resulting precipitates were collected by filtration and washed with methanol, to give the title compound (1.32 g, 41%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([CH2:23][CH3:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[CH2:23]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1)[CH3:24]
Reactant: CCc1cc(Cl)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Yield: 18.7 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 75 mg, 0.349 mmol), 4-chloro-6-ethylpyrimidine (Intermediate 12, 49.7 mg, 0.349 mmol) and DIPEA (0.122 mL, 0.697 mmol) in N-methyl-2-pyrrolidone (1 mL) were stirred in a microwave reactor at 120° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL), brine (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. This solid was dissolved in a mixture of acetonitrile and DMSO (1:1) (0.9 mL) and purified by MDAP (2 injections). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a yellow oil (21 mg);
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C1O[C:30]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)([CH2:31][CH2:32][CH2:33][Cl:34])[O:29]C1.O>C(O)CCC>[ClH:34].[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:30]([CH2:31][CH2:32][CH2:33][N:2]2[CH2:3][CH2:4][C:5]3([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[O:14][C:15]4[C:20]3=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:6][CH2:7]2)=[O:29])=[CH:40][CH:39]=1
Reactant: c1ccc2c(c1)Oc1ccccc1C21CCNCC1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: O=C(CCCN1CCC2(CC1)c1ccccc1Oc1ccccc12)c1ccc(F)cc1
Yield: 32.5 %

Procedure:
A mixture of xanthene-9-spiro-4'-piperidine hydrochloride (1 g.), potassium carbonate (1.2 g.) and γ-chloro-p-fluorobutyrophenone ethylene ketal (1.03 g.) in n-butanol is heated under reflux for 48 hours. The mixture is poured into water, extracted with ether, the ether solution evaporated and the residue warmed with 3N hydrochloric acid for 1 hour to hydrolyse the ketal. The acidic solution is extracted with ethyl acetate, the solvent evaporated and the residue recrystallised from ethyl acetate to give 1'-[3-(p-fluorobenzoyl)propyl]xanthene-9-spiro-4'-piperidine hydrochloride (0.51 g.), m.p. 219°-222° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][O:11][CH3:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[N:3]=[C:4]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:5]=[C:6]([NH:8][CH2:9][CH2:10][O:11][CH3:12])[CH:7]=2)=[CH:24][CH:23]=1
Reactant: COCCNc1cc(Cl)nc(-c2ccc(OC)cc2)n1
Reactant: Sc1ccc(Cl)cc1
Product: COCCNc1cc(Sc2ccc(Cl)cc2)nc(-c2ccc(OC)cc2)n1
Temperature: 25 °C

Procedure:
A blended mixture of 6.5 g of 4-chloro-6-(2-methoxyethylamino)-2-(4-methoxyphenyl)-pyrimidine and 15.0 g. of p-chlorothiophenol is heated to 160°C. for 3 hours. Thereafter, the reaction mixture is cooled to room temperature and triturated with 60 ml. of 30°/o sodium hydroxide. The product is separated by filtration, washed with water and recrystallized from absolute ethanol to afford 6-(4-chlorophenylthio)-4-(2-methoxyethylamino)-2-(4-methoxyphenyl)pyrimidine, m.p. 117°-118.5°C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:14][CH2:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:18][CH:17]=1>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:26][CH:27]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 2 g (15 mmol) of 4-tert-butylbenzoyl chloride with 2.9 g (15 mmol) of allyl 4-hydroxymethylbenzoate, 4 g (77%) of allyl ester are obtained in the form of a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[O:16]([C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[O:31][C:32](=[O:41])[CH:33](Br)[CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:34][CH:33]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:24]=3)[CH:6]=[N:5]2)[C:32]([OH:31])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: Oc1cccc(Oc2ccccc2)c1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(Oc3ccccc3)c2)cc1=O
Yield: 66 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 3-phenoxy-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(3-phenoxy-phenoxy)-6H-pyridazin-1-yl]-propionic acid (9.0 g, 66%); LC-MS [M+H+]=421; purity>97%, HPLC conditions: C18 column 4.6×112 mm, 5 μm, 1.0 mL/min, acetonitrile (0.1% trifluoroacetic acid) in water (0.1% trifluoroacetic acid)=100%˜50%, detector 214 nm and 254 nm. 1H-NMR (300 MHz, CDCl3): δ 1.09-1.25 (m, 2H), 1.49-1.80 (m, 7H), 2.05-2.17 (m, 1H), 2.29-2.39 (m, 1H), 5.52 (dd, J=4.5, 10.5 Hz, 1H), 6.05 (d, J=2.7 Hz, 1H), 6.73 (s, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.05-7.20 (m, 3H), 7.27-7.42 (m, 3H), 7.81 (d, J=2.7 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:16][CH:17]=2)[N:11]=1.C1C(=O)N([Br:29])C(=O)C1.O>C(Cl)Cl>[Br:29][C:9]1[O:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)c1ccc(-c2coc(-c3ccccn3)n2)cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)c1ccc(-c2nc(-c3ccccn3)oc2Br)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[5-(2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol from Step D (75 mg, 0.267 mmol) in DCM (1 mL) was added NBS (62 mg, 0.347 mmol). The reaction mixture was stirred at rt for 16 h. Water was added and the mixture extracted with DCM. The organics were dried (MgSO4), and concentrated to afford 2-[5-(5-bromo-2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol, which was used without further purification LCMS: m/z 360.0 (M+H)+.
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][NH:23][CH2:22]3.[N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[CH:45]=O.C(N(CC)CC)C.C(O)=O>C(#N)C>[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][N:23]([CH2:45][C:36]1[CH:37]=[CH:38][C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:35]=1)[CH2:22]3
Reactant: CC(=O)OCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Reactant: O=Cc1ccc2ccccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=CO
Product: CC(=O)OCC(=O)[C@@]12CN(Cc3ccc4ccccc4n3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Yield: 54.6 %

Procedure:
A solution of intermediate 6 (200 mg, 0.400 mmol), quinoline-2-carbaldehyde (251 mg, 1.600 mmol), triethylamine (61 mL, 0.440 mmol) and formic acid (263 μL, 3.20 mmol), in acetonitrile (4 ml) is irradiated with microwaves (130° C., 20 minutes). The reaction mixture was partitioned between AcOEt and 5% NaHCO3 solution. The organic layers were then washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated and the crude was purified by silica gel chromatography (DCM/MeOH 99:1) to give compound 11 (132 mg, 54.6% yield).
Reaction SMILES: [CH3:1][N:2]([C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C@H:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:4].[CH3:20]N(C)C=O.C[Br:26]>C(OCC)(=O)C>[Br-:26].[OH:11][C:7]1[CH:6]=[C:5]([C@@H:3]([N+:2]([CH3:20])([CH3:1])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:4])[CH:10]=[CH:9][CH:8]=1
Reactant: CBr
Reactant: CN(C)C=O
Reactant: C[C@@H](c1ccccc1)N(C)[C@@H](C)c1cccc(O)c1
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Product: [Br-]
Temperature: 60 °C
Yield: 89 %

Procedure:
Mix 5.1 g (0.02 mol) of 3-[(S)-1-(methyl-[(S)-1-phenylethyl]amino)ethyl]phenol (formula V) with 10 ml N,N-dimethylformamide and 7.5 g (0.08 mol) of methyl bromide at room temperature, and heat the mixture to 60° C. for 10 hours. Let it cool to room temperature and add 100 ml of ethyl acetate. A light yellow solid is produced. Filter and dry it to receive 6.5 g light yellow solid with a yield of 89%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:17]=2)=[CH:3]1.[CH3:35][N:36]([CH3:38])[CH3:37]>C(O)C>[CH3:32][S:29]([O-:31])(=[O:30])=[O:28].[CH3:35][N+:36]([CH3:38])([CH3:37])[CH2:27][CH2:26][CH2:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:15]2[C:14](=[O:33])[NH:13][C:12](=[O:34])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:17]1
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: CN(C)C
Solvent: CCO
Product: CS(=O)(=O)[O-]
Product: Cn1cc(C2=C(c3cn(CCC[N+](C)(C)C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 90 °C

Procedure:
A mixture of 173 mg of the product of Example 58 and 2 ml of a 33% solution of trimethylamine in ethanol was heated at 90° C. for 3 hours. The solvent was evaporated and the residue was purified on silica gel with dichloromethane/methanol/acetic acid/water (60:18:2:3). Trituration with ethyl acetate gave 75 mg of trimethyl [3-[3-[3-(1-methyl-3-indolyl)-2,5-dioxo-3-pyrrolin-4-yl]-1-indolyl]propyl] ammonium methylsulphonate, m.p. 180°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:65]1[CH2:69][CH2:68][C@H:67]([OH:70])[CH2:66]1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([N:65]5[CH2:69][CH2:68][C@H:67]([OH:70])[CH2:66]5)=[O:25])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: O[C@H]1CCNC1
Reactant: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30.8 %

Procedure:
To a solution of (S)-4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (0.10 g, 0.22 mmol) in DMF (2 mL) was added HATU (0.17 g, 0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.66 mmol) and the reaction was stirred for 20 minutes at ambient temperature. (S)-Pyrrolidin-3-ol (0.058 g, 0.66 mmol) was added, and the reaction was stirred for 2 hours at ambient temperature. The reaction was diluted with EtOAc (30 mL) and washed with HCl (1 N, 10 mL), NaOH (1 N, 10 mL), water (10 mL), and brine (10 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified by reverse preparative HPLC. The combined fractions were diluted with EtOAc (50 mL) and washed with 1N NaOH (10 mL), water (10 mL), and brine (10 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum to give (S)-1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-((S)-3-hydroxypyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one (0.0353 g, 0.0678 mmol, 30.6% yield). Mass spectrum (apci) m/z=521.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]#[N:14].[CH:15](N(CC)C(C)C)([CH3:17])[CH3:16].[C:24](=O)([O-:38])[O:25]N1C2C=CC=C(CC=C)C=2N=N1>C(Cl)Cl.C1COCC1>[C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][CH2:2][NH:1][C:24]([O:38][CH2:16][CH:15]=[CH2:17])=[O:25])[CH:5]=2)[NH:9][CH:8]=1)#[N:14]
Reactant: N#Cc1c[nH]c2ccc(CCN)cc12
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCc1cccc2c1nnn2OC(=O)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOC(=O)NCCc1ccc2[nH]cc(C#N)c2c1
Reaction time: 0.42 h
Yield: 94.3 %

Procedure:
To a suspension of 5-(2-amino-ethyl)3-cyano-indole (reference example 2) (925 mg, 5 mmol) in CH2Cl2/THF (20 mL, 1/1) is added N,N-diisopropylethylamine (869 mL, 5 mmol) followed by allyl-1-benzotriazolyl carbonate (1.096 g, 5 mmol). The resulting mixture is stirred for 25 minutes then concentrated. The residue is purified by flash chromatography (eluting with 7% MeOH in CH2Cl2) to give 1.27 g of product as a white solid. 1H NMR (CDCl3) d 2.92 (t, J=7 Hz, 2H), 3.50 (q, J=7 Hz, 2H), 4.53 (d, J=5 Hz, 2H), 4.79 (bs, 1H), 5.18 (d, J=10 Hz, 1H), 5.26 (d, J=17 Hz, 1H), 5.87 (m, 1H), 7.10 (dd, J=8,1 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 7.54 (s, 1H), 7.67 (d, J=1 Hz, 1H), 9.08 (bs, 1H). MS (EI) m/z 269 (M+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:23][CH2:22]3)=[N:16][CH:17]=2)[NH:12][C:11]1=[O:35].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>CN1CCCC1=O>[CH2:36]([N:12]1[C:13]2=[N:14][C:15]([NH:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([O:27][Si:28]([C:31]([CH3:32])([CH3:34])[CH3:33])([CH3:29])[CH3:30])[CH2:25][CH2:26]3)=[N:16][CH:17]=[C:18]2[CH2:19][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[Cl:3])[C:11]1=[O:35])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ncc3c(n2)N(Cc2ccccc2)C(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Sodium hydride (44 mg, 1.1 mmol (60% oil dispersion)) was added to a suspension of 3-(2-chlorophenyl)-7-(trans-4-tert-butyldimethylsilyloxycyclohexyl-amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (486 mg, 1 mmol) in 1-methyl-2-pyrrolidinone, and was stirred at room temperature for 25 minutes. To this solution was added benzyl bromide (0.12 mL 1 mmol) and stirred at room temperature for 4 hours. The reaction mixture was added to water and extracted with ethyl acetate. The layers were separated, and the organic layer was washed with water, dried with magnesium sulfate, concentrated in vacuo. The residue was purified by column chromatography using 25:75 acetone/hexane as eluant to give 1-benzyl-3-(2-chlorophenyl)-7-(trans4-tert-butyldimethylsilyloxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as an oil.
Reaction SMILES: [C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].O.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: O=C(NC(=O)N1C(=O)Cc2ccccc21)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(=O)N1C(=O)C(C(=O)c2ccco2)c2ccccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To 30 ml of N,N-dimethylformamide was added, with stirring, 2.8 g (10 mmole) of N-benzoyl-2-oxindole-1-carboxamide, followed by 2.9 g (24 mmole) of 4-(N,N-dimethylamino)pyridine. The mixture was cooled in an ice-bath and then to it was added, dropwise, with stirring, during 10 minutes, a solution of 1.6 g (12 mmole) of 2-furoyl chloride in 10 ml of N,N-dimethylformamide. Stirring was continued for 30 minutes and then the reaction mixture was poured into a mixture prepared from 250 ml of water and 8.5 ml of 3 N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was removed by filtration. The solid was recrystallized from ca. 75 ml of acetic acid to give 2.94 g of the title compound as yellow-brown crystals, mp 190° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.Cl.[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)#[N:21].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CNC(=O)Nc2cccc(C#N)c2)cc1
Reaction time: 18 h
Yield: 14.1 %

Procedure:
m-Cyanophenyl isocyanate (2.0 g, 13.9 mmol) and triethylamine (3.09 g, 30.5 mmol) in dimethylformamide (30 ml) was cooled to 0° C. and p-cyanobenzylamine hydrogen chloride (2.3 g, 13.9 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction was thawed to ambient temperature and was stirred for 18 h. The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with 1N HCl and brine, then dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on silica gel with 1:1 hexane:ethyl acetate as an eluent; there was obtained 0.54 g of pure N-(3-cyanophenyl)-N′-((4-cyanophenyl)methyl)urea; LRMS (M+H)+ m/z 294.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH2:39]([O:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=1)[CH2:40][CH2:41][CH3:42]>>[CH2:39]([O:43][C:44]1[CH:45]=[CH:46][C:47]([CH:48]([OH:49])[C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])=[CH:50][CH:51]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCCCOc1ccc(C=O)cc1
Product: CCCCOc1ccc(C(O)c2cn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c(=O)[nH]c2=O)cc1

Procedure:
5-((4-Butoxyphenyl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 4-butoxybenzaldehyde instead of benzophenone) as a colourless foam.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])C=C.[C:19]1(C)[CH:24]=CC=C[CH:20]=1>>[CH2:24]([C:14]1[C:13]([NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[OH:4])[CH:19]=[CH2:20]
Reactant: Cc1ccccc1
Reactant: C=CCOc1cc(NC(C)=O)ccc1C(=O)OC
Product: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1O
Temperature: 25 °C

Procedure:
A solution of 5 g (20.1 mmol) of the allyl ether from Example 19 in 20 ml of toluene is heated at 200° C. in a sealed tube for 24 hours. After cooling to room temperature a precipitate begins forming and the reaction mixture is cooled further to 0° C. The precipitate is filtered off and allowed to air dry, giving methyl 3-allyl-4-acetylaminosalicylate which can be used directly in the next step.