Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:27]=1)([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[N:28]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)nn4-c4ccccc4)c3)c2cc1OC
Yield: 60.3 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (92 mg, 0.31 mmol), prepared as described in Example 113A, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-isopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (100 mg, 0.31 mmol) described in the previous step. The suspension was triturated with anhydrous diethyl ether to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea (98 mg, 60%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (d, J=6.9 Hz, 6H), 2.87 (m, 1H), 3.99 (s, 6H), 6.31 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.34-7.40 (m, 3H), 7.52-7.55 (m, 6H), 8.47 (s, 1H), 8.55 (s, 1H), 9.21 (s, 1H); LC-MS (ESI) m/z 525 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)[CH3:2].S(Cl)([Cl:18])=O>O1CCOCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:18])=[O:12])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOCCOc1ccc(C(=O)O)cc1
Solvent: C1COCCO1
Product: CCOCCOc1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 7.2 g. of p-ethoxyethoxy benzoic acid, 50 ml. of dioxane and 12.2 g. of thionyl chloride was refluxed at 70° to 80° C. for 2 hours. After the reaction, excess of thionyl chloride and the solvent were recovered by a rotary evaporator to obtain a crude p-ethoxyethoxybenzoic chloride as a residue. The crude p-ethoxyethoxybenzoic acid chloride was dissolved in 70 ml. of acetone and then, a mixture of 6.6 g. of 2,3-dichloroaniline and 4.1 g. of triethylamine was added dropwise with stirring at room temperature during 30 minutes. After the addition, the mixture was stirred at the same temperature for 2 hours. After the reaction, the reaction mixture was poured into 300 ml. of 2% hydrochloric acid and the resulting precipitate was separated by a filtration. The resulting crude product was recrystallized from toluene to obtain 9.0 g. of 4-(2-ethoxyethoxy)-N-(2,3-dichlorophenyl)-benzamide. The yield was 74.4 g. The compound had a melting point of 121.2° to 122° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH2:30])=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH:30][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=2)=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cccc(OC(F)(F)F)c2)sc1C(=O)NCc1ccccc1
Yield: 28 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-trifluoromethoxybenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 28% yield; m.p. 230-232° C.; 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=7.8 Hz, 1H), 7.76 (s, 1H), 7.54-7.24 (m, 7H), 6.00 (t, J=4.8 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.38 (s, 3H); MS (ES+) m/z 436.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1Br.BrCC.[Mg].C[O:16][B:17](OC)[O:18]C.Cl>CCOCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[B:17]([OH:18])[OH:16]
Reactant: COB(OC)OC
Reactant: Clc1cc(Cl)c(Cl)c(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: CCBr
Solvent: CCOCC
Product: OB(O)c1cc(Cl)cc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of 2,3,5-trichlorobromobenzene (8.60 g, 0.033 mole) in dry ether (33 ml) and bromoethane (4.73 ml, 7.31 g, 0.067 mole) was added dropwise to a suspension of magnesium turnings (2.80 g, 0.12 mole) in dry ether (21.50 ml) at room temperature. The mixture was refluxed for 0.50 hr and cooled to room temperature. The mixture was then added dropwise under nitrogen to a solution of trimethylborate (5.16 ml, 5.16 g, 0.05 mole) in dry ether (8.60 ml) maintaining the temperature below −60° C. This was warmed to room temperature overnight, then cooled in an ice-bath and treated with 2M hydrochloric acid (10 ml). The ether layer was separated, washed with water (2×20 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 4.57 g (61%), M.p. 257-260° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14]([OH:17])(=O)=[O:15])([O-:3])=[O:2].S(Cl)([Cl:20])=O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14]([Cl:20])(=[O:17])=[O:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1S(=O)(=O)Cl

Procedure:
In a similar fashion using route 39 general procedure 96, 2-nitro-5-trifluoromethyl-benzenesulfonic acid 453 (700 mg, 2.58 mmol), thionyl chloride (7 ml) and (0.1 ml) DMF at 90° C. for 3 h gave the title compound (730 mg) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][NH:22][C:23]2=[O:29].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([C:7]2[C:2]([NH:17][C:18]3[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][NH:22][C:23]4=[O:29])=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:13][CH:12]=1
Reactant: Fc1ncccc1-c1ncnc2[nH]ccc12
Reactant: Cc1ccc2c(=O)[nH]ccc2c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(=O)[nH]ccc2c1Nc1ncccc1-c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.1 %

Procedure:
A mixture of 4-(2-fluoropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (463 mg, 2162 μmol) and 5-amino-6-methylisoquinolin-1(2H)-one (377 mg, 2162 μmol) in THF (1.5 mL) was sonicated for 5 min until all the solid was mixed well. Lithium bis(trimethylsilyl)amide (9.7 mL, 9.72 mmol; 1 M in THF) was added via a syringe and the reaction tube was sonicated and stirred at RT for 5 min. The reaction was heated to 120° C. in a microwave for 20 min. The reaction mixture was cooled to rt and partitioned between DCM and NaHCO3. The aqueous layer was washed with DCM three times. The combined organic layers were washed with brine and dried over Na2SO4, then concentrated in vacuo. The residue was purified via flash column on silica (MeOH-DCM=0.5-6%) to give a light brown solid 5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1(2H)-one (550 mg, 69% yield). MS (ESI, pos. ion) m/z: 369
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:11][CH:12]([CH3:14])[CH3:13].[OH:15]O>C(O)(=O)C.O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[O:15]
Reactant: Cc1cc(O)c(SCC(C)C)c(=O)o1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(O)c(S(=O)CC(C)C)c(=O)o1
Yield: 95 %

Procedure:
To a solution of 4-hydroxy-3-isobutylthio-6-methyl-2-pyrone (8.0 g., 0.0374 mole) in glacial acetic acid (50 ml.) was added 30% hydrogen peroxide (4.3 g., 0.0374 mole). The solution was allowed to stand for several days and then was diluted with water, filtered and the cake dried, yielding 8.2 g. (95 percent) of the desired product. Recrystallization from hexane gave the pure product as an off-white solid, m.p. 102°-103°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16]C(OC(C)(C)C)=O)[CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[C:37]12([CH2:47][CH2:48][NH2:49])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2.C(N(CC)C(C)C)(C)C.Cl>O1CCOCC1.CO.CN(C)C=O>[ClH:1].[NH2:16][CH:13]1[CH2:14][CH2:15][N:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=2)[C:4]([NH:49][CH2:48][CH2:47][C:37]23[CH2:46][CH:41]4[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]4)[CH2:38]2)[CH2:44]3)=[O:6])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)O)c2)C1
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(Cl)c(C(=O)NCCC34CC5CC(CC(C5)C3)C4)c2)C1
Yield: 43.2 %

Procedure:
Prepared as described in example 74 above using (+/−)-2-chloro-5-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-pyrrolidinyl]-benzoic acid (0.090 g), 1,1′-carbonyldiimidazole (0.043 g), tricyclo[3.3.1.13,7]decane-1-ethanamine, hydrochloride salt (0.057 g), N,N-diisopropylethylamine (0.046 ml) and dimethylformamide (3 ml). This compound was treated with 4N hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to yield the title compound (0.025 g).
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:29][N:30](C)[C:31](=O)OC(C)(C)C)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[O:21][CH2:22][C:23]([NH:25][CH:26]3[CH2:27][CH2:28]3)=[O:24])(=[O:13])=[O:14])[CH:10]=[C:9]([CH2:29][NH:30][CH3:31])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl ((5-(cyclohex-1-en-1-yl)-1-((3-(2-(cyclopropylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 7e (97 mg, 0.22 mmol) was dissolved in 8 mL of dichloromethane, and the reaction solution was cooled in an ice bath, followed by dropwise addition of 2 mL of trifluoroacetic acid. After removing the ice bath, the reaction solution was stirred at room temperature for 2 h. A saturated sodium bicarbonate solution was added dropwise until the pH of the reaction solution was 7 to 8, and then it was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system A to obtain the title product 2-(3-((2-(cyclohex-1-en-1-yl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-cyclopropylacetamide 7 (67 mg, a light yellow oil) in 85% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=4)[CH2:32][CH2:33]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
85 mg (63%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 1-(4-methoxyphenyl)piperazine (50 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[CH2:20][N:21]1[CH:25]=[N:24][C:23]([NH2:26])=[N:22]1>>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([NH:26][C:23]2[N:24]=[CH:25][N:21]([CH2:20][C:19]3[CH:27]=[C:28]([F:31])[C:29]([F:30])=[C:17]([F:16])[CH:18]=3)[N:22]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Nc1ncn(Cc2cc(F)c(F)c(F)c2)n1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2ncn(Cc3cc(F)c(F)c(F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 1b) starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole (WO2009076352) and 1-(3,4,5-trifluoro-benzyl)-1H-[1,2,4]triazol-3-ylamine from example 17a). The title compound was obtained as a colorless foam (Yield=49%). MS ISP (m/e): 415.2 (100) [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([CH2:20][O:21][CH3:22])[O:14]2)=[C:6]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:5]=1.[CH3:38][C:39]([CH3:41])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:6]2[N:5]=[C:4]([CH2:3][CH2:2][NH:1][CH:39]([CH3:41])[CH3:38])[N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([CH2:20][O:21][CH3:22])[O:14]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNC(C)C)nc32)[C@H](O)[C@@H]1O
Yield: 41.9 %

Procedure:
The title compound was prepared by a similar method to example 12 using (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 11) (120 mg, 0.24 mmol), acetone (14 mg, 0.24 mmol), acetic acid (16 mg, 0.27 mmol) and sodium triacetoxyborohydride (75 mg, 0.35 mmol) to afford the title compound as a solid (55 mg). MS: 547 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1>S(Cl)(Cl)=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Cc1ccc(C(=O)O)c(OCc2ccccc2)c1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(CO)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of 4-methyl-2-phenylmethoxy-benzoic acid (30.3 g, 0.125 mol) in 100 ml thionyl chloride containing 3 drops DMF was heated under reflux for 30 min. The SOCl2 was removed under vacuum and the residual oil was diluted with 100 ml dry benzene. The solvent was again removed under vacuum to remove remaining traces of SOCl2 and the crude acid chloride product was added slowly to a solution of NaBH4 (10 g) in dry diglyme (200 ml) at 10°-20° C. The resulting mixture was stirred for 30 min at room temperature and the solvent was removed under vacuum by heating in an oilbath. Water (100 ml) was added slowly to the white solid and then acetic acid (10 ml) was added to ensure complete decomposition of the excess borohydride. The mixture was basified with conc. ammonia and extracted with ethyl acetate to give 4-methyl-2-phenylmethoxybenzenemethanol (26.6 g, 93% crude yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl[Si](C)(C)[CH3:15]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[OH:11])[C:5]([O:7][CH3:15])=[O:6]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1cc(O)c(O)c(Cl)c1
Solvent: CO
Product: COC(=O)c1cc(O)c(O)c(Cl)c1
Yield: 81.6 %

Procedure:
A solution of 3-chloro-4,5-dihydroxybenzoic acid (2) (3.16 g, 16.76 mmol) and chlorotrimethylsilane (6.36 mL, 50.3 mmol) in MeOH (50 mL) was stirred at 50° C., under nitrogen overnight. The solvent was removed in vacuo and the residue was partitioned between brine (75 mL) and EtOAc (75 mL). The organic layer was washed with brine (75 mL), dried over MgSO4 and filtered. The solvent was removed in vacuo to give methyl 3-chloro-4,5-dihydroxybenzoate (3) (3.26 g, 13.68 mmol, 82% yield): m/z 201 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.17 (2H, br s), 7.38 (1H, d), 7.35 (1H, d), 3.78 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:11].C(N(CC)CC)C>ClCCl>[N:1]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:10]=[O:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN=C=O
Temperature: 7.5 °C
Reaction time: 4 h
Yield: 302.6 %

Procedure:
Into a 500-mL 3-necked round-bottom flask was placed tert-butyl 2-aminoacetate (135.1, 5.9 g, 44.98 mmol, 1.00 equiv). Then dichloromethane (180 mL) and ditrichloromethyl carbonate (4.43 g, 14.93 mmol, 0.33 equiv) were added at 0° C. After 30 min triethylamine (13.65 g, 134.89 mmol, 3.00 equiv) was added to the above mixture. The resulting solution was stirred for 4 h at 5-10° C. in a water/ice bath. The solids were filtered out. The filtrate was concentrated under vacuum. The resulting solution was diluted with 50 mL of ethyl ether. The solids were filtered out. The resulting mixture was concentrated under vacuum. Purification afforded 7.1 g (crude) of tert-butyl 2-isocyanatoacetate (135.2) as a yellow oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH3:18][Si:19]([CH3:46])([CH3:45])[CH2:20][CH2:21][O:22][CH2:23][N:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([C:33]3[CH:34]=[N:35][N:36]([CH:38]4[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]4)[CH:37]=3)[C:27]=2[CH:26]=[CH:25]1>C1COCC1>[CH3:18][Si:19]([CH3:46])([CH3:45])[CH2:20][CH2:21][O:22][CH2:23][N:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([C:33]3[CH:34]=[N:35][N:36]([CH:38]4[CH2:43][CH2:42][C:41](=[CH:9][C:7]#[N:8])[CH2:40][CH2:39]4)[CH:37]=3)[C:27]=2[CH:26]=[CH:25]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCC(=O)CC4)c3)ncnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCC(=CC#N)CC4)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.0 M potassium tert-butoxide in THF (1.90 mL) at 0° C. was added a solution of diethyl cyanomethylphosphonate (321 μL, 0.00198 mol) in THF (4 mL) dropwise. The reaction was held for 10 min, then it was added to a solution of 4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanone (743 mg, 0.00180 mol) in THF (5 mL) stirring at 0° C. under a nitrogen atmosphere. The reaction was stirred 1.5 h at rt. LCMS analysis showed clean conversion to the desired product. To the reaction mixture was then added water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extract was washed with water, then sat'd NaCl, then dried over Na2SO4, and concentrated to dryness to yield 0.76 g of a white crystalline solid (TLC (EtOAc) Rf 0.33). The product was purified by automatic flash chromatography on silica gel. Used 40 g column; flow 40 mL/min; [A=hexane] [B=EtOAc]; A, 2 min; Gradient to B in 20 min. Rotary evaporation yielded 0.70 g of a white crystalline solid (89% yield). 1H NMR (CDCl3) δ 8.9 (s, 1H); 8.3 (s, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.9 (d, 1H); 5.7 (s, 2H); 5.3 (s, 1H, olefin); 4.5 (m, 1H, NCH); 3.6 (m, 2H); 3.2 (m, 1H); 2.7 (m, 1H); 2.5 (m, 4H); 2.1 (m, 2H); 1.0 (m, 2H); −0.1 (s, 9H). MS(ES) 435 (M+1).
Reaction SMILES: Cl[CH:2](Cl)[C:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.CCOCC>C(O)C.C(OCC)(=O)C>[CH2:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])[CH3:2]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Solvent: CCOCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (4.74 g.) was refluxed in ethanol (175 ml.) for 60 minutes; the mixture was filtered and the filtrate evaporated to give an oil. Trituration with ethyl acetate gave a solid (354 mg.), which was discarded. The ethyl acetate solution was extracted with sodium bicarbonate solution; the aqueous layer was then acidified and extracted with ethyl acetate. On drying and evaporation this solution gave a gum (3.34 g.), which was redissolved in hot ethyl acetate. Addition of a fourfold volume of ether gave a solid, which was discarded. The filtrate was concentrated and set aside at 0°; a white solid (548 mg.) crystallised out, m.p. 160°-165° (decomp.), [α]D25 = 157° (c 0.7, tetrahydrofuran) λλmax (NaHCO3 solution) 237nm (ε = 12,800), 260nm (ε = 8,000), νmax (CHBr3) 1770 (β-lactam), 1720 (COOH), 1659 and 1678 cm-1 (CONH). N.M.R. spectrum (D2O, with sodium bicarbonate) -O-CH2.CH3 systems centred at 6.5 and 8.83τ. (Found: C, 50.6; H, 4.8; N, 7.1; S, 16.3. C16H18N2O5S 2 requires C, 50.2; H, 4.7; N, 7.4; S, 16.8%). RF = 1.5 (System C), 1.35 (System B).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:6]=2[CH:7]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[Na+].[Cl-]>CN(C)C=O>[I:12][C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:2][O:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:6]=2[CH:8]=1
Reactant: Oc1ccccc1
Reactant: BrCc1cc2cc(I)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccc2oc(COc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.5 %

Procedure:
To an N,N-dimethylformamide (20 mL) solution of 2-bromomethyl-5-iodo-benzofuran (270 mg, 0.801 mmol) and phenol (113 mg, 1.2 mmol) was added potassium carbonate (332 mg, 2.4 mmol). This mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into sat. NaCl and extracted with ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate followed by concentrating under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to obtain the title compound (251 mg, 90%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:10][CH:11]=1.[N:19]1(CC2N=CC(O)=CC=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.BrCCCCl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N:13]1([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:11][N:10]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: ClCCCOc1ccc(CN2CCCCC2)nc1
Reactant: Oc1ccc(CN2CCCCC2)nc1
Agent: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1cc(CN2CCCCC2)ncc1OCCCN1CCCCC1
Temperature: 25 °C
Yield: 80 %

Procedure:
5-(3-Chloro-propoxy)-2-Piperidin-1ylmethyl-pyridine. A solution of 6-piperidin-1-ylmethyl-pyridin-3-ol (0.225 g, 1.17 mmol), 1-bromo-3-chloro propane (0.23 mL, 2.34 mmol), and K2CO3 (0.483 g, 3.50 mmol) in acetone (10 mL) was heated to reflux temperature. After 10 h the reaction mixture was cooled to rt, diluted with acetone (50 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated, giving the crude title compound as an oil (0.250 g, 80%).