Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH3:24]
Reactant: CCCCNS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCN(CC(=O)OCC)S(=O)(=O)c1ccc(C)cc1

Procedure:
Dissolve N-butyl-4-methyl-benzenesulfonamide (10 mmol) in tetrahydrofuran (50 mL) and treat with sodium hydride (10 mmol). Stir the reaction for 30 minutes and add ethyl bromoacetate (10 mmol). Stir the reaction at reflux for 18 hours. Then add methylene chloride (100 mL) and rinse with water (100 mL), brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate to provide crude ethyl-[butyl-(toluene-4-sulfonyl)-amino]-acetate.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:16]1)=O)(C)(C)C.C=O.C([BH3-])#N.[Na+]>C(Cl)Cl>[C:39]([Si:36]([CH3:38])([CH3:37])[O:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([C@@H:17]3[CH2:18][CH2:19][N:15]([CH3:13])[CH2:16]3)=[CH:21][CH:22]=2)(=[O:27])=[O:28])=[CH:34][CH:33]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2)C1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC[C@@H](c2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of (S)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-benzenesulfonyl]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (342 mg, 0.661 mmol) in DCM (5 mL) under argon atmosphere. The mixture was stirred at room temperature for 75 minutes, then solvent was evaporated under reduced pressure. The crude material (482.9 mg) was dissolved in acetonitrile (5 mL) and to the resulting solution, under argon atmosphere, was added formaldehyde (37% in water, 0.264 mL, 3.292 mmol) followed by sodium cyanoborohydride (82.4 mg, 1.316 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, then buffered to pH 12. The resulting mixture was extracted with DCM, and the combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 248.2 mg (87% yield) of (S)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-benzenesulfonyl]-phenyl}-1-methyl-pyrrolidine as a colorless oil which solidified upon standing.
Reaction SMILES: [F:1][C:2]1[C:3]([O:33]C)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]3[C:15]=1[CH:16]=[N:17][C:18]([CH3:25])=[N:19]3)[C:7]([C:27]([F:30])([F:29])[F:28])([OH:26])[CH2:6][C:5]2([CH3:32])[CH3:31].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[CH:8]([NH:13][C:14]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]4[C:15]=3[CH:16]=[N:17][C:18]([CH3:25])=[N:19]4)[C:7]([C:27]([F:28])([F:29])[F:30])([OH:26])[CH2:6][C:5]([CH3:31])([CH3:32])[C:4]=2[C:3]=1[OH:33]
Reactant: COc1c(F)c(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2nc(C)ncc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc2c(NC3c4cc(C)c(F)c(O)c4C(C)(C)CC3(O)C(F)(F)F)ccc(F)c2n1
Temperature: 2.5 °C
Yield: 61.5 %

Procedure:
111.2 mg (0.231 mmol) of (rac.)6-fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen -2-ol is mixed at 0° C. with 3.2 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for one and one-half hours at 0 to 5° C. At 0° C., saturated sodium bicarbonate solution is now carefully added in drops. After 10 minutes of vigorous stirring at room temperature, the batch is extracted three times with ethyl acetate. The organic phases are dried, and after the solvent is spun off, the residue is chromatographed on a Flashmaster. 66.4 mg (61.5%) of the desired compound is isolated.
Reaction SMILES: C(OC([CH:6]1[C:12](=[O:13])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=O)C.[ClH:21]>>[ClH:21].[NH:9]1[CH2:8][CH2:7][CH2:6][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Product: O=C1CCCNCC1

Procedure:
20 g 5-Oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester was stirred over night at 110° C. in 200 mL 6 M hydrochloric acid. The reaction was concentrated to yield 11 g of the desired product. Rf: 0.20 (dichlormethane/methanol=9/1), (M+H)+=114
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.[CH:15]([O-:17])=[O:16].[Na+].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13][O:17][CH:15]=[O:16]
Reactant: O=C[O-]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=COCc1c(Cl)ccc2cc(Cl)cnc12
Yield: 84 %

Procedure:
24.5 parts by weight of 3,7-dichloro-8-chloromethylquinoline and 13 parts by weight of sodium formate in 220 parts by weight of dimethylsulfoxide are heated for 6 hours at 100° C. The mixture is then cooled, water is added and the precipitated product is filtered off under suction and recrystallized from toluene. 21.5 parts by weight (84% of theory) of 3,7-dichloro-8-formyloxymethylquinoline of melting point 146° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>>[C:7]([N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)(=[O:9])[CH3:8]
Reactant: Cc1c[nH]cn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1cnc(C)c1
Yield: 68.9 %

Procedure:
The 1-Acetyl-4-methylimidazole intermediate was prepared by making a mixture of 4-methylimidazole (82.1 g, 1.0 mol)) and acetic anhydride (190 mL, 2.0 mol) and refluxing for 15 min after which time 150 mL of solvent was removed by distillation at atmospheric pressure (head temperature 125° C.) over a 1 h period. The remaining acetic anhydride was removed at 50° C./0.5 mm and the residual liquid was crystallized from ether (150 mL) at -20° C. to give 85.5 g of 1-acetyl-4-methylimidazole product, m.p. 49°-51° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH:6]([C:11]2[CH:12]=[C:13]([N:18]3[CH:22]=[N:21][N:20]=[CH:19]3)[CH:14]=[C:15]([F:17])[CH:16]=2)[C:7]([F:10])([CH3:9])[CH3:8])[CH2:3]1.Br[CH:24]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].C(N(C(C)C)CC)(C)C>CC#N>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH:24]([N:2]2[CH2:3][CH:4]([CH:6]([C:11]3[CH:12]=[C:13]([N:18]4[CH:19]=[N:20][N:21]=[CH:22]4)[CH:14]=[C:15]([F:17])[CH:16]=3)[C:7]([F:10])([CH3:9])[CH3:8])[CH2:5]2)[C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:38][CH:37]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)(F)C(c1cc(F)cc(-n2cnnc2)c1)C1CNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(F)C(c1cc(F)cc(-n2cnnc2)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
A sample of 135 mg (0.41 mmole) of 4-[3-(1-Azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorophenyl]-4H-1,2,4-triazole hydrochloride, 211 mg (0.62 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile and 181 uL (1.025 mmole) of diisopropylethylamine in 5 mL of dry CH3CN was heated at reflux for 3 h. The solution was concentrated and the residue was dissolved in 20 mL of CH2Cl2 and 5 mL of NaHCO3. The layers were separated and the organic phase was dried over Na2SO4 and concentrated. The residue was purified on silica gel using CH2Cl2-EtOAc—NH3 (2M in MeOH), 200:50:4 to afford the title compound as a mixture of 4 diastereomers: Mass Spectrum: m/e=518 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C@H:22]([C@@H:27]4[O:31]C(C)(C)O[C:28]4=[O:34])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C@H:16]([CH3:35])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:36][OH:37]>CC(O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C@H:27]([OH:31])[C:28]([NH:36][OH:37])=[O:34])=[O:21])[C@H:16]([CH3:35])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cc2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Reactant: NO
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cc2)C[C@H]1C)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a suspension of (5S)-5-((1S)-1-{[(2R)-4-(4′-fluorobiphenyl-4-yl)-2-methylpiperazin-1-yl]carbonyl}-3-methylbutyl)-2,2-dimethyl-1,3-dioxolan-4-one (230 mg, 0.48 mmol, 1.0 eq) in a mixture of iPrOH (4 mL) and THF (4 mL) was added a 50% aq. solution hydroxylamine (0.08 mL, 1.43 mmol, 3.0 eq). The reaction mixture was stirred at rt for 8 h. Evaporation of the solvent gave a white solid. This product was washed with iPr2O (2×), filtered and dried under vacuum to give the title compound as a white powder (89%). M−(EST): 456.3; M+(ESI): 458.4. HPLC (Condition A), Rt: 3.9 min (HPLC purity: 97.5%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:31])[C@:7]1([OH:30])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:27])([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:29])(=[O:3])[CH3:2].N1C=CN=C1.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6](=[O:31])[C@:7]1([O:30][Si:38]([CH3:40])([CH3:39])[CH3:37])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:27])([C@@H:22]([O:26][Si:38]([CH3:40])([CH3:39])[CH3:37])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(O[Si](C)(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.9 %

Procedure:
To a solution of (11β,16β)-9-fluoro-11,17-dihydroxy-16-methyl-3,20-dioxopregna-1,4-dien-21-yl acetate (18.79 g, 43.25 mmol) and imidazole (58.89 g, 864.9 mmol) in 200 mL of dry N,N-dimethylformamide was added neat trimethylsilyl chloride (55.0 mL, 433 mmol) dropwise during 15 min. The resulting pale yellow solution was stirred at room temperature for 16 hours. The solution was diluted with ethyl acetate and washed successively with water, sat. NH4Cl, water, sat. NaHCO3, water, and brine. The organic phase was dried over Na2SO4, filtered and evaporated in vacuo to yield 26 g of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[O:28]>ClCCl>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:27]([NH:26][CH3:25])=[O:28])[CH:10]=4)[CH2:6][CH2:7]3)[CH2:13][CH2:14]2)=[CH:23][CH:22]=1
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2

Procedure:
1-(6-Aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (3 g) was dissolved in dichloromethane (140 ml) and methylisocyanate (0.53 g) was added. The solution was refluxed for 4 hours. Dichloromethane was evaporated and the remaining crude title compound was purified by column chromatography on silica gel (eluted with 4% triethylamine in ethyl acetate). The pure title compound 5a crystallized from diethyl ether. Yield: 0.8 g, mp: 170-173° C. 1H NMR (CDCl3): δ 1.70-1.90 (m, 5 H); 2.00-2.15 (m, 2 H); 2.20-2.35 (m, 1 H); 2.35-2.55 (m, 2 H); 2.60 (dd, 1 H); 2.80 (d, 3 H); 2.75-2.95 (m, 2 H); 3.05 (broad d; 2 H); 3.30 (qui, 1 H); 4.95 (q, 1 H); 6.55 (s, 1 H); 6.90-7.00 (m, 3 H); 7.10-7.25 (m, 3 H); 7.35 (s, 1 H)
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Clc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[Br:8].[N:23]1[CH:28]=[CH:27][N:26]=[C:25]2[S:29][C:30]([C:32](Cl)=[O:33])=[CH:31][C:24]=12>O1CCOCC1.O>[Br:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:18])[CH3:19])[CH:12]=2)=[CH:3][C:2]=1[NH:1][C:32]([C:30]1[S:29][C:25]2=[N:26][CH:27]=[CH:28][N:23]=[C:24]2[CH:31]=1)=[O:33]
Reactant: O=C(Cl)c1cc2nccnc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(N)c2)c1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(NC(=O)c3cc4nccnc4s3)c2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of N-(3-amino-4-bromophenyl)-3-(2-cyanopropan-2-yl) 62 (215 mg, 0.600 mmol) and thieno[2,3-b]pyrazine-6-carbonyl chloride 63 (238 mg, 1.2 mmol) in dioxane (1 mL) was stirred for 2 h in microwave at 100° C. The reaction mixture was poured out in water, precipitate filtered off and washed with water and dried. Crystallization with acetonitrile gave crude compound 64 (340 mg, 109%). A sample of compound 64 was purified by HPLC to give the title compound N-(2-bromo-5-(3-(2-cyanopropan-2-yl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 64. NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 7.62 (t, d=7.8 Hz, 1H), 7.72-7.80 (m, 3H), 7.96 (d, J=7.8 Hz, 1H), 8.06 (m, 2H), 8.57 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.90 (d, J=2.3 Hz, 1H), 10.55 (s, 1H), 10.76 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[C:19]([C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=1)[C:24](N(OC)C)=[O:25])#[N:20].Cl>C1COCC1.O>[Cl:11][C:9]1[C:8]([O:12][CH3:13])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([C:24](=[O:25])[C:23]2[CH:30]=[CH:31][CH:32]=[C:21]([C:19]#[N:20])[CH:22]=2)[CH:10]=1
Reactant: COc1cc(C(=O)O)c(Br)cc1Cl
Reactant: CON(C)C(=O)c1cccc(C#N)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)c(C(=O)c2cccc(C#N)c2)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A −78° C. solution of 2-bromo-4-chloro-5-methoxybenzoic acid (0.5 g, 1.88 mmol) in THF (15 mL) was treated with n-BuLi (1.6M in hexane) (1.7 ml, 2.82 mmol) and stirred for 1 h at −78° C. 3-Cyano-N-methoxy-N-methylbenzamide (0.35 g, 1.88 mmol) in THF (15 mL) was added dropwise and the reaction stirred for 1 h at −78° C., then overnight at rt. It was diluted with water (30 mL), acidified with 5N HCl (15 mL), and extracted with EtOAc (2×100 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain 4-chloro-2-(3-cyanobenzoyl)-5-methoxybenzoic acid (0.5 g, 84%) (316.33 [M−H]).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[F:19])=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Reactant: O=C(Cl)c1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C(=O)c3ccccc3F)c(O)cc21

Procedure:
26.6 g of finely pulverised aluminium chloride are suspended in 60 ml of methylene chloride. While stirring and while cooling slightly, 9.61 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester, dissolved in a small amount of methylene chloride, are added dropwise at room temperature. After stirring for 30 minutes at room temperature, 15.85 g of o-fluorobenzoyl chloride are added dropwise thereto and the resulting reaction mixture is heated at reflux for 4 hours. After cooling, the reaction mixture is poured onto ice and extracted thoroughly with methylene chloride. The combined organic phases are washed with water, dried over magnesium sulphate and concentrated by evaporation. The yellow oily residue (20 g) is chromatographed over 400 g of silica gel with methylene chloride. Fractions 7-16 (50 ml fractions) are combined and concentrated. The residue is crystallised from ether/petroleum ether. 4-(o-fluorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester is obtained in the form of yellow crystals having a melting point of 59°-61°.
Reaction SMILES: [NH:1]=[C:2]1[N:6]=[C:5]([N:7]([CH3:9])[CH3:8])[S:4][S:3]1.[C:10]([N:14]=[C:15]=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>O1CCCC1>[C:10]([NH:14][C:15]([N:1]=[C:2]1[N:6]=[C:5]([N:7]([CH3:9])[CH3:8])[S:4][S:3]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CN(C)c1nc(=N)ss1
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)c1nc(=NC(=O)NC(C)(C)C)ss1

Procedure:
A suspension of 4.75 parts of the hydrobromide salt of 3-imino-5-dimethylamino-3H-1,2,4-dithiazole, two parts of t-butyl isocyanate, two parts of triethylamine, and 50 parts of tetrahydrofuran was stirred and refluxed for two days. The reaction mixture was cooled and the insoluble triethylammonium bromide was removed by filtration and discarded. The filtrate was then evaporated under reduced pressure leaving a white solid, which was recrystallized from isopropanol to afford 3.4 parts of 1-t-butyl-3-(5-dimethylamino-3H-1,2,4-dithiazol-3-ylidene)urea, m.p. 174°-177°C. dec.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[C:6]([Cl:17])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[K].[C:25]1([CH2:31][CH2:32][S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O.O>[Cl:17][C:6]1[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=[C:2]([NH:36][S:33]([CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:34])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1
Reactant: COc1cccc(Oc2c(Cl)nc(N3CCOCC3)nc2Cl)c1
Reactant: NS(=O)(=O)CCc1ccccc1
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(Oc2c(Cl)nc(N3CCOCC3)nc2NS(=O)(=O)CCc2ccccc2)c1
Yield: 90.3 %

Procedure:
A solution of 4-[4,6-dichloro-5-(3-methoxy-phenoxy)-pyrimidin-2-yl]-morpholine (1.0 g) and 2-phenyl-ethanesulfonic acid amide potassium salt (1.57 g, Referential Example 1e) in DMSO (15 ml) was stirred at 60° C. for 24 h. The solution was diluted with water (75 ml) and extracted twice with diethyl ether (75 ml) before it was acidified with 10% aq. citric acid. The mixture was extracted twice with EA (150 ml). The organic phase was washed with water (50 ml). The product precipitated upon evaporation of the solvent. The solid was collected, washed with diethyl ether and dried to give 2-phenyl-ethanesulfonic acid [6-chloro-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide (1.28 g) as off-white powder. LC-MS: tR=5.34 min, [M+1]+=505.12, [M−1]−=502.97.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[OH-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:16][CH:18]1[O:20][CH2:19]1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: ClCC1CO1
Reactant: O=C1CCc2cc(Cl)c(O)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2cc(Cl)c(OCC3CO3)cc2N1
Reaction time: 3 h

Procedure:
20.0 grams of 6-chloro-7-hydroxy-3,4-dihydrocarbostyril and 3.7 g of sodium hydroxide are mixed with 100 ml of methanol and stirred for 3 hours, then 150 ml of epichlorohydrin is added thereto and heated for 5 hours under refluxing conditions. After the reaction is completed, the reaction mixture is concentrated under reduced pressure to dryness. The residue thus obtained is mixed with 100 ml of 2N-sodium hydroxide and stirred well. The insoluble matter is separated by filtration, washed with water and dried. The crude crystals thus obtained are recrystallized from methanol-ethanol to obtain 19.7 g of 6-chloro-7-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril in the form of colorless crystals with a melting point of 190°-192° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[N:54]([C:57]1[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=1[C:59]#[N:60])=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:55]([NH:54][C:57]2[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=2[C:59]#[N:60])=[O:56])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: N#Cc1ccccc1N=C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1NC(=O)N1CC[C@@H](CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 77 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 2-isocyanatobenzonitrile as the starting materials in 77% yield. LCMS for C31H29ClN9O2 (M+H)+: m/z=594.1.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[CH:11][N:10]([C@@H:13]3[O:33][C@H:32]([CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:23]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:14]3[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[NH2:43][NH2:44]>C(OCC)(=O)C>[NH:43]([C:2]1[C:3]2[CH:12]=[CH:11][N:10]([C@@H:13]3[O:33][C@H:32]([CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:23]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:14]3[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1)[NH2:44]
Reactant: NN
Reactant: CSc1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Solvent: CCOC(C)=O
Product: CSc1nc(NN)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reaction time: 2 h

Procedure:
A mixture of 55 g of 4-chloro-2-methylmercapto-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 500 ml of anhydrous hydrazine is heated under reflux and a nitrogen atmosphere for two hours, evaporated in vacuo, and coevaporated with xylenes. The residue is distributed between a mixture of ethyl acetate and water and the aqueous layer reextracted with ethyl acetate. The dried ethyl acetate extracts are combined and evaporated in vacuo to provide 51 g of crude syrupy product. Chromatography of this material over silica gel and ethyl acetate provides 49 g of pure 4-hydrazino-2-methylmercapto-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow syrup.