Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][NH:36][C:37]1[S:41][N:40]=[C:39]([CH3:42])[CH:38]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:32][O:33][CH2:34][CH2:35][N:36]([C:37]1[S:41][N:40]=[C:39]([CH3:42])[CH:38]=1)[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Reactant: COCCNc1cc(C)ns1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1cc(C)ns1

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid and (2-methoxy-ethyl)-(3-methyl-isothiazol-5-yl)-amine with triethylamine and diethyl cyanophosphonate in dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1C.N1C=CC=C[CH:14]=1.[F:19][C:20]([F:33])([F:32])[S:21]([O:24]S(C(F)(F)F)(=O)=O)(=[O:23])=[O:22].O>ClCCl>[F:19][C:20]([F:33])([F:32])[S:21]([O:24][C:7]1[C:6]([CH3:14])=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[CH3:1])(=[O:23])=[O:22]
Reactant: c1ccncc1
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F

Procedure:
A solution of 150 g (0.9 mol) of dimethylnitrophenol in 700 ml of dichloromethane is cooled to −15° C. 181 ml of pyridine are added. 308.8 g (1.09 mol) of trifluoromethanesulphonic anhydride are then metered in dropwise over a period of 2 h in such a way that the reaction temperature does not exceed −5° C. Then, at a temperature of −5° C., 150 ml of water are added. The organic phase is extracted successively with HCl (1 molar, about 300 ml) and water (twice), each at 3-5° C. The solvent is removed in vacuo, and the residue is stirred with petroleum ether. The precipitate is filtered off with suction. A further fraction is obtained by cooling the mother liquor. Yield: 232 g (85%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: Nc1ccccc1
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Product: Cc1cccc(Cl)c1C(=O)Nc1ccccc1

Procedure:
In one embodiment, the step comprises combining 2-chloro-6-methylbenzoyl chloride with aniline to afford 2-chloro-6-methyl-N-phenylbenzamide. In one embodiment, the step is optionally carried out in the presence of a base (e.g., an amine base such as Et3N).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][CH:15]([C:18]([OH:20])=O)[CH2:16][Cl:17])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl.[CH3:22][O:23][C:24](=[O:28])[CH:25]([CH3:27])[NH2:26].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(Cl)Cl>[CH3:22][O:23][C:24](=[O:28])[CH:25]([CH3:27])[NH:26][C:18](=[O:20])[CH:15]([CH2:16][Cl:17])[NH:14][C:12](=[O:13])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:10][CH:9]=1
Reactant: C=CCOc1ccc(CC(=O)NC(CCl)C(=O)O)cc1
Reactant: COC(=O)C(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOc1ccc(CC(=O)NC(CCl)C(=O)NC(C)C(=O)OC)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-(DL)-alanine (0.622 g) was dissolved in dry tetrahydrofuran (10 ml). To the solution was added (DL)-alanine methyl ester hydrochloride (0.3 g) in dry methylene chloride (3.0 ml) containing dry triethylamine (0.3 ml). DCC (0.413 g) was added and the reaction mixture was stirred at room temperature. After being stirred overnight, the reaction mixture was worked up. DCU was filtered off. The volatile material was evaporated at reduced pressure. The semi-solid residue was dissolved in chloroform (20 ml). The chloroform solution was washed with aqueous hydrochloric acid (0.5 M, 2×20 ml), saturated aqueous sodium bicarbonate solution (2×20 ml) and finally with water (2×20 ml). The extract was dried (anhydrous sodium sulphate). The solvent was evaporated at reduced pressure to leave a small volume of material. Light petroleum (b.p. 60°-80° C.) was added to obtain a solid product (400 mg) of m.p. 100°-105° C. After recrystallisation from chloroform/light petroleum (b.p. 60°-80° C.) the above-named product, (200 mg), m.p. 105°-107° C., was obtained.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH3:15])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].FC(F)(F)C(O)=O.N[C@H](C(N[C@H](C(OCC1C=CC=CC=1)=O)C)=O)CC(C)C.FC(F)(F)C([O-])=O.Cl>CCOCC.C(OCC)(=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH3:15])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)CN)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
Boc-Gly-Leu-Ala-OBzl was prepared by coupling Boc-Gly-OH (5.70 g, 32.6 mmoles) to H-Leu-Ala-OBzl using the mixed anhydride procedure described in Example 2. The product (13.8 g) was obtained as an amorphous solid. Boc-Gly-Leu-Ala-OBzl was deblocked with trifluoroacetic acid by the procedure described for the preparation of H-Leu-Ala-OBzl except that the trifluoroacetate salt was soluble in ether. The preparation was dissolved in ethyl acetate and treated with anhydrous hydrogen chloride. The resulting product was precipitated by the addition of ether to yield 7.7 g of H-Gly-Leu-Ala-OBzl .HCl in a first crop.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:19]/[C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=1)/[CH2:5]2
Reactant: COc1cc2c(cc1Br)CCC2=O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C/C(=C\c1cccc(C(F)(F)F)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A solution of 11 (200 mg, 0.829 mmol) in toluene was added 3-(trifluoromethyl)benzaldehyde 99 (158.86 mg, 0.9128 mmol). PTSA (285.5 mg, 172.20 mmol) was added to the reaction mass. The reaction was stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 152 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-5-bromo-6-methoxy-2-(3-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one 152 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[CH2:24]([Si](C)(C)C)[CH:25]=C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)[CH3:32]>C(C#N)(C)=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:18]([O:17][C@H:16]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]([O:7][C:8](=[O:10])[CH3:9])[C@H:5]([CH3:32])[O:22][C@H:21]1[CH2:23][CH:24]=[CH2:25])(=[O:20])[CH3:19]
Reactant: CC(=O)O[C@@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CC[Si](C)(C)C
Agent: CC(=O)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC[C@@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-tetra-O-acetyl-α-L-fucopyranose (12 g, 36.1 mmol) and allyltrimethyl silane (11.48 mL, 72.2 mmol) in AcCN (60 mL) at 0° C. was added TMS-OTf (3.52 mL, 19.50 mmol). The reaction mixture was stirred at 0° C. for 18 hr and then at rt for 6 hr. The resulting red solution was diluted with CH2Cl2 (250 mL) and sat'd NaHCO3 (150 mL) was added carefully. The aqueous layer was separated and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (220 g), eluting with 15% EtOAc in hexanes to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 1.16 (d, J=6.4, 3H), 2.04 (s, 3H), 2.08 (s, 3H), 2.18 (s, 3H), 2.34 (m, 1H), 2.57 (m, 1H), 4.00 (m, 1H), 4.29 (dt, J=10.4, 7.3, 1H), 5.13 (m, 2H), 5.23 (dd, J=10.0, 3.4, 1H), 5.30 (dd, J=3.4, 1.9, 1H), 5.35 (dd, J=10.0, 5.6, 1H), 5.77 (m, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=3)=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[C:29]1([C:35]2([OH:41])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[ClH:1].[C:23]1([C:20]2[N:19]=[C:18]([C:14]3[N:15]=[CH:16][C:17]4[N:5]([CH2:4][CH2:3][CH2:2][N:38]5[CH2:37][CH2:36][C:35]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)([OH:41])[CH2:40][CH2:39]5)[C:6]5[C:11]([C:12]=4[CH:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=5)[O:22][N:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: ClCCCn1c2ccccc2c2cc(-c3nc(-c4ccccc4)no3)ncc21
Solvent: CN(C)C=O
Product: Cl
Product: OC1(c2ccccc2)CCN(CCCn2c3ccccc3c3cc(-c4nc(-c5ccccc5)no4)ncc32)CC1
Yield: 43 %

Procedure:
The compound was synthesized by mixing (Compound 9) (0.7 g, 1.8 mmol), 4-phenylpiperidin-4-ol (0.38 g, 2.2 mmol) and TEA (0.55 g, 5.4 mmol) in DMF, in the same manner as illustrated in example 4 to give the title compound (0.47 g, 43%). M.p. 184°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:26][CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29].C(N(CC)CC)C>O1CCCC1>[OH:29][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: NCC(O)c1ccccc1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCNCC(O)c2ccccc2)ccc1Cl
Temperature: 80 °C
Yield: 34.8 %

Procedure:
2-Chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide from Example 63 (0.1 g), 2-amino-1-phenylethanol (0.539 g) and triethylamine (0.5 ml) were dissolved in tetrahydrofuran (3 ml) and heated at 80° C. for 60 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, the residue was suspended in aqueous sodium hydrogen carbonate (30 ml), the product was extracted into ethyl acetate (3×30 ml), dried over magnesium sulphate filtered and concentrated under reduced pressure. Purification by NPHPLC eluting with 0 to 25% ethanol in dichloromethane gave title compound as a white solid (0.044 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9]C.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([OH:9])[CH:4]=[CH:5][C:6]=1[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[C:12]([F:11])[CH:13]=1)=[O:16]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1cccc(F)c1)c1ccc(O)c(Cl)c1Cl

Procedure:
The Friedel-Crafts reaction described in the foregoing examples is repeated with 2,3-dichloroanisole, 3--fluorobenzoyl chloride and AlCl3 to yield 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]([NH:15][NH2:16])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:6][C:5]1[N:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:16]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C(C)(C)C)n1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
A mixture of 12.5 g of 4,4-dimethyl-3-oxopentanenitrile, 25 g of tert-butylhydrazine hydrochloride, and 27.6 g of potassium carbonate in 400 mL of ethanol was refluxed for 24 h. The mixture was cooled to 25° C. and then it was filtered. The solvent was evaporated from the filtrate and the residue was partitioned between ethyl acetate and distilled water. The organic phase washed with brine and dried (MgSO4). The solvent was evaporated at reduced pressure and the residue was dissolved in a small volume of ether. The mixture was diluted with an equal volume of hexanes and then the volume of the solution was reduced by one half by evaporation at reduced pressure. The white solid which precipitated was collected by filtration to give 8.7 g of 5-Amino-1,3-di(tert-butyl)pyrazole 17. 1H-NMR (CDCl3): δ 5.43 (s, 1H), 1.62 (s, 9H), 1.25 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH:19]([C:22]1[O:26][CH:25]=[N:24][C:23]=1[C:27](O)=[O:28])([CH3:21])[CH3:20]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:23]3[N:24]=[CH:25][O:26][C:22]=3[CH:19]([CH3:21])[CH3:20])=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: CC(C)c1ocnc1C(=O)O
Product: CC(C)c1ocnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)c1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-isopropyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=397.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14]4=[C:15]([CH2:17][N:18](C(OCC5C=CC=CC=5)=O)[CH2:19][CH2:20][N:13]4[CH2:12][CH:11]4[CH2:31][CH2:32][CH2:33][CH:10]34)[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1.[OH-].[Na+].C(Cl)[Cl:53]>O>[ClH:53].[C:1]1([C:7]2[CH:8]=[C:9]3[C:14]4=[C:15]([CH2:17][NH:18][CH2:19][CH2:20][N:13]4[CH2:12][CH:11]4[CH2:31][CH2:32][CH2:33][CH:10]34)[CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCl
Reactant: O=C(OCc1ccccc1)N1CCN2CC3CCCC3c3cc(-c4ccccc4)cc(c32)C1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COc1ccccc1
Product: Cl
Product: c1ccc(-c2cc3c4c(c2)C2CCCC2CN4CCNC3)cc1
Reaction time: 0.75 h

Procedure:
The compound of example 21 (0.255 g, 0.581 mmol) was dissolved in methylene chloride (0.89 mL). To the solution of Example 21 was added trifluoromethane sulfonic acid (0.360 mL, 11.3 mmol) and anisole (0.190 mL, 1.74 mmol) at room temperature. After 45 minutes, the pH of the reaction mixture was adjusted to a pH of 9 to 10 with 1N NaOH, and then methylene chloride and water were added to the reaction flask. The contents of the flask were then transferred to a separatory funnel and extracted with methylene chloride (4×). The combined organic extracts were then dried with magnesium sulfate, filtered and concentrated. Further purification (10% ammonia in 2M solution of ethanol/ethyl acetate) yielded 0.157 g of the free amine product with some baseline impurities (80%). To purify further, the free amine was dissolved in diethyl ether/isopropanol, and then HCl in 2M solution of diethyl ether (1 eq) was added. After 30 minutes, the resulting precipitate was filtered to give the desired product.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:9]([N:12]([CH2:16][C:17]#[CH:18])[C:13](Cl)=[O:14])[CH2:10][CH3:11].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:16]([N:12]([CH2:9][C:10]#[CH:11])[C:13]([N:6]1[CH:7]=[N:8][C:4]([S:3][CH2:1][CH3:2])=[N:5]1)=[O:14])[CH2:17][CH3:18]
Reactant: CCSc1nc[nH]n1
Reactant: C#CCN(CCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCN(CCC)C(=O)n1cnc(SCC)n1

Procedure:
A mixture of 6.45 g. 3-ethylthio-1,2,4-triazole, 8.1 g. N-propyl-N-prop-2-ynylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 24 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride, to give a residual oil. This residual oil was distilled under reduced pressure to give 1-(N-propyl-N-prop-2-ynylcarbamoyl)-3-ethylthio-1,2,4-triazole, b.p. 124°C./0.05 mm. (97.8% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>ClCCl>[CH3:17][S:18]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccccc1F
Reaction time: 3 h

Procedure:
To a solution of 2-Fluorobenzyl alcohol (10 g, 79.28 mmol) in dry dichloromethane (200 ml) was added triethylamine (12.03 g, 118.9 mmol) under argon at room temperature. Methanesulfonyl chloride (10.71 g, 93.5 mmol) was added to the above reaction mixture at 0° C., and stirring was continued for another 3 hours. Water (100 ml) was added to the reaction mixture and the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and brine. The reaction mixture was dried over Na2SO4, filtered and concentrated to give the title compound as an yellow oil which was used without further purification.
Reaction SMILES: C[C:2]([OH:5])([CH3:4])[CH3:3].[CH3:6][OH:7].[C:8]1([CH3:14])C=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:6][O:7][C:11]1[CH:12]=[C:4]2[C:8]([CH2:14][CH2:3][C:2]2=[O:5])=[CH:9][CH:10]=1
Reactant: CO
Reactant: Cc1ccccc1
Reactant: CC(C)(C)O
Product: COc1ccc2c(c1)C(=O)CC2
Yield: 80 %

Procedure:
An oven-dried flask was charged with β-keto methyl ester (1.0 mmol), Bu2SnO (26 mg, 0.1 mmol, 0.1 eq.), tBuOH (5 mL) and toluene (15 mL). The flask was connected a Dean-Star trap which continuingly removed methanol while refluxing. tBuOH (2 mL) was added when the mixture of alcohols and toluene was released through Dean-Star trap. The mixture was refluxed for 4 hours. The resultant yellow solution was concentrated on a water evaporator. The residue was directly loaded on silica gel column for purification (hexanes/EtOAc 20/1) to give β-keto tButylester (80-84% yield) as a white solid (6-methoxyindanone) and a purple solid (5-chloroindanone), respectively. For 5-chloroindanone ester (84%) 22D: 1H NMR (CDCl3, 400 MHz) (85% keto ester form): δ ppm 7.68 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 3.63 (dd, J=8.0, 4.0 Hz, 1H), 3.48 (dd, J=17.2, 4.0 Hz, 1H), 3.31 (dd, J=17.2, 4.0 Hz, 1H), 1.49 (s, 9H). (15% enol form): δ ppm 10.25 (br s, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J=7.6 Hz, 1H), 3.46 (s, 2H), 1.57 (s, 9H). 3C NMR (CDCl3, 100 MHz) (keto and enol forms): δ ppm 198.46, 167.85, 155.07, 141.77, 133.88, 128.50, 127.18, 126.70, 125.59, 125.01, 121.38, 82.28, 54.39, 32.71, 29.99, 28.42, 27.96. FT-IR (ν, cm−1): 2980 (m), 2933 w), 1716 (s, with a shoulder at 1745), 1649 (m), 1601 (m), 1369 (m), 1260 (m), 1154 (s). For 6-methoxyindanone ester (80%) 22C: 1H NMR (CDCl3, 400 MHz) (90% keto ester form): δ ppm 7.38 (d, J=8.0 Hz, 1H), 7.20 (m, 2H), 3.83 (s, 3H), 3.64 (dd, J=8.0, 3.6 Hz, 1H), 3.40 (dd, J=16.8, 3.6 Hz, 1H), 3.26 (dd, J=16.8, 8.0 Hz, 1H), 1.49 (s, 9H). (10% enol form): δ ppm 10.52 (br s, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 6.96 (dd, J=8.4, 2.0 Hz, 1H), 3.85 (s, 3H), 3.40 (s, 2H), 1.57 (s, 9H). 13C NMR (CDCl3, 100 MHz) (keto and enol forms): δ ppm 199.94, 168.32, 159.53, 146.53, 136.56, 127.11, 124.64, 105.48, 81.92, 55.53, 55.04, 29.62, 28.41, 27.94. FT-IR (ν, cm−1): 2980 (m), 1709 (s, with a shoulder at 1740), 1645 (m), 1494 (m), 1277 (m), 1149 (s), 1028 (m).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:25][CH2:24]C(=O)[CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:27](O)(=O)C.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:20]3[CH2:25][CH2:24][C@@H:31]([N:32]4[CH2:37][CH2:36][N:35]([CH3:27])[CH2:34][CH2:33]4)[CH2:22][CH2:21]3)[CH:9]=2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Reactant: CN1CCNCC1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2cn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone (2.25 g, 6.5 mmol), acetic acid (1.17 g, 19.5 mmol) and N-methylpiperazine (1.95 g, 19.5 mmol) were dissolved in dichloroethane (200 ml). Sodium triacetoxyborohydride (2.07 g, 9.75 mmol) was added portionwise and the mixture stirred at room temperature overnight. Saturated sodium bicarbonate solution (150 ml) was added and the aqueous layer extracted with dichloromethane (3×100 ml). The combined organics were washed with water, dried (sodium sulphate), filtered and evaporated to leave a semi-solid whaich was purified by flash silica gel column chromatography using CH2Cl2/methanol (0% MeOH to 50% MeOH in 5% increments). The fractions corresponding to the faster running material were combined and evaporated to give cis-5-(4-amino-3-methoxyphenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.2 g, 43%) as a cream solid. 1H NMR (d6-DMSO): δ 8.1(1H, s), 7.11 (1H, s), 6.87(1H, s), 6.79(1H, d), 6.05(2H, bs), 4.80(2H, bs), 4.64(1H, m), 4.08(1H, m), 3.82(3H, s), 3.17(2H, m), 2.37(6H, m), 2.21(3H, s), 2.08(4H, m), 1.70(2H, m), 1.53(2H, m). HPLC (rt=11.24 min, 97.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]([C:15]#[N:16])([CH3:14])[CH3:13].[OH-].[Li+].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]([C:15]#[N:16])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc(Cl)c(C(C)(C)C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cc(C(=O)O)ccc1Cl
Yield: 97.3 %

Procedure:
To a solution of methyl 4-chloro-3-(1-cyano-1-methylethyl)benzoate (8.0 g, 34 mmol) in tetrahydrofuran (30 mL) were added lithium hydroxide.monohydrate (2.13 g, 51 mmol), methanol (100 mL) and water (5 mL), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (200 mL). 1N Hydrochloric acid was slowly added to the mixture to adjust the pH to 3. The precipitated white precipitate was collected by filtration, washed with water, and dried to give the title compound (7.4 g, 99%) as a white powder.