Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH:2]=1.[CH3:16][O:17][C:18](=[O:45])[CH:19]=[CH:20][CH:21]([NH:37]C(OC(C)(C)C)=O)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>>[CH3:16][O:17][C:18](=[O:45])[CH2:19][CH2:20][CH:21]([NH:37][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)C=CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(O)CCCC/C=C/c1cccnc1
Product: COC(=O)CCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1cccnc1
Yield: 26 %

Procedure:
Isolated as a gum from (E)-7-Pyridin-3-yl-hept-6-enoic acid 76 (137 mg, 0.67 mmol) and (RS)-5-(4-Benzyloxy-phenyl)-4-tertbutoxycarbonylamino-pent-2-enoic acid methyl ester RS-40 (250 mg, 0.61 mmol) to afford the title compound (79.4 mg, 26%) as a gum: chromatographed on silica using 70:30 EtOAc:petroleum. 1H nmr (CDCl3) δ 1.30 (m, 4H), 1.49-1.82 (m, 5H), 1.82-1.95 (m, 1H), 2.08 (t, J=8 Hz, 2H), 2.34 (m, 2H), 2.59 (t, J=8 Hz), 2.69 (dd, J=7, 14 Hz, 1H), 2.77 (dd, J=7, 14 Hz, 1H), 3.65 (s, 3H), 4.15 (m, 1H), 5.03 (s, 2H), 5.36 (br d, J=9 Hz, 1H), 6.90 (d, J=9 Hz, 2H), 7.9 (d, J=9 Hz, 2H), 7.17-7.52 (m, 7H), 8.42 (br s, 2H). ESMS 503 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>CCO.O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[NH:13][CH3:12]
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
2-Fluoro-3-chloronitrobenzene (3.0 g, 17 mmol) was dissolved in EtOH (6 mL) and Methylamine 40% in Water (6 mL) was added dropwise at 0° C. and mixture was warmed up to RT overnight. Mixture went to a dark orange precipitate within 10 min. The solid was isolated by filtration, rinsed with water (2*10 mL) and dried in a desiccators under vacuum to afford 3 g of 2-chloro-N-methyl-6-nitrobenzenamine (Yield: 90%) as an orange crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:49])[CH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)[CH3:30]>>[CH2:29]([O:31][C:32](=[O:49])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)=[CH:6][CH:7]=2)=[CH:36][CH:35]=1)[CH3:30]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)COCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-trifluoromethyl-benzyloxy)-ethanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:20][C:2]([F:19])([F:1])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[O:23][CH2:22][CH2:21][O:18]2)=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c2ccccc12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(Oc1ccc(C2OCCO2)c2ccccc12)C(F)(F)F

Procedure:
A solution of 4-trifluoromethylsulfonyloxy naphthaldehyde (4.09 g, 13.4 mmol), ethylene glycol (1.5 mL, 1.67 g, 26.9 mmol), and p-toluene sulfonic acid (250 mg) in toluene (250 mL) was refluxed for 16 hr using a Dean-Stark trap. The solution was allowed to reach room temperature, was washed with satd. NaHCO3-sol. (2×80 mL), brine (80 mL), dried (MgSO4), and concentrated to give a yellow oil (4.79 g, quant).
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[C:1]1([C:7]2([C:17]3[CH:18]=[CH:19][C:14]([OH:20])=[CH:15][CH:16]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: OC1(c2ccccc2)CCCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
A mixture of 5 g (28.4 mmol) of 1-phenyl-1-cyclohexanol, 5.35 g (56.8 mmol) of phenol and 250 mg (1.32 mmol) of toluenesulfonic acid monohydrate was stirred at 85° C. under nitrogen atmosphere for 4 hours. The material was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine. The resulting solution was dried (Na2SO4), filtered and concentrated to a white solid which was heated under high vacuum to remove residual phenol. The resulting residue was purified by flash chromatography on silica gel, eluting with methanol/dichloromethane to provide 5.64 g (22.4 mmol) of 4-(1′-(phenyl)cyclohexyl)phenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[C:12]([O:21][CH3:22])=[CH:13][C:14]([O:19][CH3:20])=[C:15]([CH:18]=2)[CH:16]=O)=[CH:5][N:4]=1.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[C:12]([O:21][CH3:22])=[CH:13][C:14]([O:19][CH3:20])=[C:15](/[CH:16]=[CH:24]/[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[O:25])[CH:18]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(-c2cc(C=O)c(OC)cc2OC)c(OC)n1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1ncc(-c2cc(/C=C/C(=O)c3ccc(C(=O)O)cc3)c(OC)cc2OC)c(OC)n1
Yield: 22 %

Procedure:
The title compound was prepared by condensing 5-(2,4-dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-benzaldehyde (Ex-38A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 203–205° C., 22% yield. 1H-NMR (DMSO-d6) δ 8.11–9.15 (m, 3H), 7.99–8.06 (m, 3H), 7.88 (s, 1H), 7.76 (d, J=17 Hz, 1H), 6.76 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H) 3.81 (s, 3H). MS m/z=451 ([M+H]+). HRMS (ES+) Calcd. for C24H22N2O7: 451.1505. Found: 451.1524.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[NH:19][C:18]2[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24]/[C:25](=[N:28]/[H])/[NH:26]O)[C:15](=[O:30])[N:14]([CH2:31][CH2:32][CH3:33])[C:13]=2[N:12]=1>CS(C)=O>[Cl:10][C:11]1[NH:19][C:18]2[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[N:26]=[C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:9][N:28]=3)[C:15](=[O:30])[N:14]([CH2:31][CH2:32][CH3:33])[C:13]=2[N:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCC)c1=O)NO
Solvent: CS(C)=O
Product: CCCn1c(=O)n(CCCCc2noc(-c3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 1.9 %

Procedure:
Benzoic acid (9 mg, 0.074 mmol) and CDl (13 mg, 0.081 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(8-Chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (28 mg, 0.081 mmol) was added and the mixture was stirred at 80° C. for 4 h. The mixture was purified by MDAP to give the title compound as a white solid (0.6 mg, 2%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:17][C:18]([N:20]([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:4].[CH3:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>>[CH2:15]([O:14][C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:17][C:18]([N:20]([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:3](=[O:4])[CH2:2][NH:1][C:36]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=1)=[O:37])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Product: CCOC(=O)c1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 52.3 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with 2-[2-amino-N-(2-ethoxycarbonylphenyl)acetamido]-N-methyl-N-phenylacetamide (2.25 g) and 3-methylphenyl isocyanate (0.88 g), and after recrystallisation in ethyl acetate, 2-{N-(2-ethoxycarbonylphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-N-methyl-N-phenylacetamide (1.6 g), m.p. 201° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Cl.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][N:13]1[CH2:18][CH2:17][N:16]([CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(CCl)cc1OC
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(Cc3ccc(OC)c(OC)c3)CC2)cc1OC
Temperature: 97.5 °C
Reaction time: 8 h

Procedure:
3,4-dimethoxybenzyl chloride (10 g, 53.6 mmol) was combined with piperazine (2.3 g, 26.8 mmol) in anhydrous DMF (30 ml) and heated with stirring under nitrogen for 8 hours at 95-100° C. The cooled reaction mixture was diluted with water (100 ml) and acidified to pH 1 with concentrated hydrochloric acid. The white precipitate was collected by filtration and washed with water (50 ml). The solid was resuspended in water (50 ml) and the pH adjusted to >9 by the dropwise addition of sodium hydroxide solution (50% NaOH in water). The resultant white solid was collected by filtration and dried under vacuum at 50° C., yield 10 g.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.NC1CCN(CC2C=CC3C(=CC=CC=3)C=2)CC1>C(N(CC)CC)C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][CH:2]=[N:3][CH:4]=3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: NC1CCN(Cc2ccc3ccccc3c2)CC1
Solvent: CCN(CC)CC
Product: c1ncc2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[4-1-(2-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(2-naphthyl)methylpiperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH2:10][C:11]([CH3:19])([CH3:18])[C:12](=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:20][C:21]([NH:23]C(=O)C1C=CC=CC=1)=[O:22])#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:9][CH2:10][C:11]([CH3:19])([CH3:18])[C:12]([NH:13][CH2:14][CH2:15][CH3:16])=[O:17])[NH:20][C:21](=[O:22])[N:23]=1
Reactant: CCCNC(=O)C(C)(C)COc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCNC(=O)C(C)(C)COc1cccc2[nH]c(=O)nc(N)c12
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A solution of N-(2-cyano-3-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-phenylcarbamoyl)benzamide (example 222a) (141 mg, 0.3 mmol) and NaOH (2 N, 0.3 mL) in EtOH (5 mL) was stirred at 100° C. under nitrogen for 2 hrs. After cooling to room temperature, the clear reaction solution was filtered, and the filtrate was carefully neutralized with 10% AcOH with vigorous stirring at 0° C. The resultant precipitate was collected by filtration, washed with water and then 20% EtOH in water to give the final product (81 mg) in 76% yield as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.73 (t, J=7.4 Hz, 3H), 1.21 (s, 6H), 1.33-1.41 (m, 2H), 3.01 (q, J=7.4 Hz, 2H), 4.08 (s, 2H), 6.64 (d, J=8.0 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.79 (t, J=7.4 Hz, 1H), 7.84 (s, 1H), 10.60 (s, 1H). MS 319 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])(=O)C.[NH4+].[O-:15][C:16]#[N:17].[K+]>Cl.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:16]([NH2:17])=[O:15])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: N#C[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)Nc1cc(Cl)ccc1O
Reaction time: 8 h

Procedure:
2-amino-4-chlorophenol (1.3 g, 8.9 mmol) was dissolved in 1M HCl (10 mL). Ammonium acetate was added to the solution to adjust pH to 5. The stirred mixture was treated with a suspension of potassium cyanate (0.80 mg, 9.8 mmol) in water, and than kept overnight at room temperature. Water was removed by evaporation and the residue was recrystallized from water to afford pink precipate (0.9 g, 55%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[N:11](C2CCCCO2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][C@@H:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[N:13]=2>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[NH:15][C:14]([O:20][C@@H:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:13]2
Reactant: CCCC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Yield: 102.8 %

Procedure:
Trifluoroacetic acid (2.3 ml, 3.40 g, 29.9 mmol) was added to a stirred solution of 8-(methyloxy)-2-{[(1S)-1-methylpentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.479 g, 4.23 mmol) in methanol (25 ml). The resultant mixture was stirred for 66 hours under an atmosphere of nitrogen and then evaporated and dried in vacuo to give the title compound as a white solid (1.65 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9](Br)[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:37]([Si:39]([CH3:42])([CH3:41])[CH3:40])#[CH:38]>C1(C)C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([C:38]#[C:37][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: [Cu]I
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C#C[Si](C)(C)C)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (200 mg, 0.36 mmol), ethynyltrimethyl silane (184 mg, 1.87 mmol), Pd(PPh)3Cl2 (26 mg, 0.036 mmol), CuI (17 mg, 0.087 mmol) and TEA (0.26 mL, 1.87 mmol) in toluene (5 mL) was sealed in a microwave vile and purged with N2 three times. The resulting mixture was heated at 80° C. for 2 hr before diluted with EA (20 mL) and water (20 mL). The layers were separated. The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica gel, 0 to 100% EA in PE) to afford (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-6-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (110). The product was then dissolved in MeOH (5 mL) and KF was added to the solution. The resulting mixture was stirred at r.t. for 30 min and then concentrated in vacuo. The residue was diluted with DCM (10 mL) and water (10 mL). The layers were separated. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford (R)-tert-butyl 3-(4-amino-6-ethynyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (111) (70 mg, 39% yield) as a yellow oil. LC-MS (ESI): m/z (M+1) 496.1.
Reaction SMILES: I[Si](C)(C)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14]([NH:15][C@H:16]3[C@@H:20]([CH3:21])[CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH2:17]3)=[C:13]([C:32](=[O:34])[NH2:33])[CH:12]=[N:11][N:10]2[CH:35]=1.BrC1C=C2C(Cl)=C(C(N)=O)C=NN2C=1.N[C@H]1[C@@H](C)CN(C(OCC2C=CC=CC=2)=O)C1>C(#N)C>[Br:6][C:7]1[CH:8]=[C:9]2[C:14]([NH:15][C@H:16]3[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]3)=[C:13]([C:32]([NH2:33])=[O:34])[CH:12]=[N:11][N:10]2[CH:35]=1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Agent: C[Si](C)(C)I
Agent: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CC#N
Product: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reaction time: 2 h

Procedure:
Iodotrimethylsilane (6.23 mL, 45.8 mmol) was added dropwise to a suspension of (3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (8.65 g, 18.31 mmol, prepared by coupling Intermediate 2 and enantiopure Intermediate 5 as previously described in Example 52) in acetonitrile (60 mL). The resulting mixture turned to a homogeneous solution several minutes after completion of addition and gradually turned to brown suspension. After 2 h at room temperature, the resulting mixture was quenched with methanol (10 mL), stirred for 5 min and concentrated in vacuo. The solid residue was diluted with ether (80 mL) and dichloromethane (80 mL), stirred for 30 min and filtered. The filter cake was washed with ether-dichloromethane (1:1 mixture, 160 mL), and dried under vacuum to give the desired 6-bromo-4-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide as yellow powder, assumed as HI salt (10.64 g). 1H NMR (400 MHz, methanol-d4) δ ppm 8.20 (s, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 5.03-4.92 (m, 1H), 3.83-3.72 (m, 1H), 3.67 (dd, J=12.0, 7.8 Hz, 1H), 3.49-3.40 (m, J=2.4 Hz, 1H), 3.14 (t, J=11.3 Hz, 1H), 2.85-2.71 (m, J=7.3 Hz, 1H), 1.25 (d, J=7.0 Hz, 3H); MS (ES+) m/z: 338.0 (M+H); LC retention time: 2.485 min (analytical HPLC Method H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH2:14]O)[CH:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>C1COCC1>[Br:40][CH2:14][C:12]1[CH:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:13]=1
Reactant: COC(=O)c1cc(CO)cc(-c2ccccc2Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CBr)cc(-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
187 mg (0.68 mmol) of the compound from Example 111A and 266 mg (1.01 mmol) of triphenyl-phosphine were dissolved in 6 ml of THF, and 336 mg (1.01 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr, the filter cake was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). This gave 275 mg (>100% of theory) of the target compound, which were immediately reacted further.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:22]=[CH:21][C:13]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][O:16][C:12]=2[C:11]=1[CH2:23][CH2:24][CH3:25])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[NH:32]1[CH2:39][CH2:38][C:36](=[O:37])[NH:35][C:33]1=[O:34]>CN(C=O)C>[CH2:23]([C:11]1[C:12]2[O:16][N:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[C:13]=2[CH:21]=[CH:22][C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6][N:32]1[CH2:39][CH2:38][C:36](=[O:37])[NH:35][C:33]1=[O:34])[CH2:24][CH3:25]
Reactant: O=C1CCNC(=O)N1
Reactant: CCCc1c(CCCCOS(C)(=O)=O)ccc2c(C(F)(F)F)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(CCCCN2CCC(=O)NC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
A mixture of 4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butyl methanesulfonate (60 mg, 0.16 mmol), from this Example step 5, Cs2CO3 (206 mg, 0.63 mmol) and 5,6-dihydrouracil (54.2 mg, 0.48 mmol) in dry DMF (1.5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. Combined organic extracts were washed with water and brine, dried over Na2SO4 and the solvent evaporated in vacuo. The residue was purified by preparative TLC using ethyl acetate to give the title compound.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4](C)C.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.N[C@H](C(O)=O)CC1N=CNC=1.N1C=CC(=O)NC1=O.[O:44]=[CH:45][C@@H:46]([C@H:48]([C@@H:50]([C@@H:52]([CH2:54][OH:55])[OH:53])[OH:51])[OH:49])[OH:47].[OH-].[Na+].OP(O)(O)=O>C(O)C>[CH:7]([OH:9])([OH:8])[CH2:2][CH2:3][CH3:4].[O:44]=[CH:45][C@@H:46]([C@H:48]([C@@H:50]([C@@H:52]([CH2:54][OH:55])[OH:53])[OH:51])[OH:49])[OH:47]
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: CCCC(O)O

Procedure:
One liter fermenters were prepared with 540 mL of medium containing (per L): 6.7 g yeast nitrogen base without amino acids (DIFCO, product #291940); 0.2 g L-leucine; 0.04 g L-tryptophan; 2.8 g yeast synthetic drop-out medium supplements without histidine, leucine, tryptophan and uracil (Sigma, product #Y2001); and 10 mL ethanol. D-glucose (50% w/w) was added fed-batch so that concentration, initially at 30 g/L, varied between 30 and 5 g/L. Temperature was controlled at 30° C. and pH was maintained at pH 5.5 with the addition of either 50% (w/w) NaOH or 20% (w/v) H3PO4. Air was sparged at 0.3 standard liters per min without back pressure and the minimum stir speed was set to 100 rpm. dO was 100% initially and rpm was programmed to control dO at 30%, however, oxygen demand was low and the dO of all fermenters (Runs #1-3 in Table 5) remained in the 90% range throughout the phase of air sparging. In two fermenters (duplicate Runs #2-3), nitrogen sparge replaced air sparge at 35 hrs into the run. Over the course of the fermentations, samples were withdrawn for cell mass (OD600), substrate utilization and by-product distribution measurements. Substrate and by-product concentrations were determined from HPLC analysis. The results are summarized in Table 4, below. Despite the difference in gas sparging between the fermenters, the results were not significantly different. Butanediol (BDO, sum of meso-butanediol and ±-butanediol) was produced at an average concentration of 229 mM with a molar selectivity of 0.63 (mole butanediol produced/moles glucose consumed). The molar selectivity obtained in shake flasks was identical to that obtained in fermenters.