Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=3)=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH2:53][CH:54]=[O:55])[N:10]=2)[N:5]=1)[CH3:3].N1CC[O:59][CH2:58][CH2:57]1.C([BH3-])#N.[Na+]>C(O)C.CO>[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31]([C:33]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=3)=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH2:53][C:54]([O:59][CH2:58][CH3:57])=[O:55])[N:10]=2)[N:5]=1)[CH3:3]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OCC=O)ccc2n1
Reactant: C1COCCN1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)COc1ccc2nc(CC)cc(OCc3ccc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)c2n1
Reaction time: 20 h
Yield: 23.9 %

Procedure:
A saturated solution of hydrogen chloride in ethanol (0.1 ml) was added to a solution of compound B (600 mg) and morpholine (450 mg) in methanol (10 ml) containing 3A molecular sieves (1 g). Sodium cyanoborohydride (53 mg) was added and the mixture was stirred for 20 hours. Volatile material was removed by evaporation and the residue purified by flash chromatography, eluting with methanol/ethyl acetate (1:9 v/v). to give 2-ethyl-6-[2-(4-morpholino)ethoxy]-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (A) (152 mg), m.p. 135°-137° C. (after trituration with hexane); NMR (d6 -DMSO): 1.3(t, 3H), 2.3-2.45(m, 4H), 2.6-2.8(m, 2H), 2.85(q, 2H), 3.4-3.55(m, 4H), 4.45-4.6(m, 2H), 5.4(s, 2H), 6.8-6.9(m, 6H), 7.1-7.7(complex m, 18H), 7.8(dd, 1H), 8.15(d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: CN1CCN(CCCCN)CC1
Solvent: CCOCC
Product: CN1CCN(CCCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)CC1
Temperature: 170 °C
Reaction time: 0.03 h

Procedure:
A mixture of 0.152 g (0.43 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 0.50 g (2.90 mmol) of 1-(4-aminobutyl)-4-methylpiperazine was heated with stirring in a 170° C. oil bath. After 2 minutes, solution was complete. After 2 hours, the solution was cooled to room temperature, and the dark gum was dissolved in 25 mL of ether. The solution was washed with 4×5 mL of water. Most of the color went into the water wash. The ether solution was dried over potassium carbonate, filtered, and concentrated to ca. 2 mL volume. The crystals that separated on inducement were filtered and washed with ether; wt 0.063 g; mp 130°-132° C.;
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:22]([CH2:24][Cl:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.C(Cl)(Cl)Cl>O1CCCC1>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@H:22]([OH:23])[CH2:24][Cl:25])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
3.5 g of sodium borohydride were added to an ice-cooled stirred solution of 21 g of [N-(benzyloxycarbonyl)-L-phenylalanyl]methyl chloride in 500 ml of aqueous tetrahydrofuran. Stirring was continued for 0.5 hour and the solvent was removed by evaporation. The residue was partitioned between dichloromethane and water and then carefully acidified with concentrated hydrochloric acid. After working-up the organic phase gave a white solid which ran as two spots: Rf 0.4 and 0.5 (5% methanol/chloroform). The solids were extracted with boiling hexane until all of the higher running component had been extracted. The combined n-hexane extracts were evaporated and the residue was re-extracted with boiling n-hexane to remove a small amount (0.5 g) of the lower running component. In this manner there were obtained 11.5 g of 3(S)-(benzyloxyformamido)-1-chloro-4-phenyl-2(S)-butanol of melting point 151°-153° C. (from ethyl acetate/n-hexane).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1([CH3:29])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([Se:16][C:17]#[C:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH:7]=[CH:6][C:5]1=2.C(OCC)C.O.Cl>C1COCC1.O.CO>[CH3:3][C:4]1([CH3:29])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]2[CH:9]=[C:8]([Se:16][C:17]#[C:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH:7]=[CH:6][C:5]1=2
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Lithium hydroxide (440 mg) is added to a solution of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate (740 mg, 1.74 mmol), obtained in Example 4, in 15 ml of THF and 2 ml of a water/methanol mixture (1/1). The reaction medium is refluxed for 8 h. It is then poured into an ethyl ether/water mixture, acidified to pH 1 with concentrated hydrochloric acid solution and extracted with ethyl ether. After separation of the phases by settling, the organic phase is washed twice with water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The residue is recrystallized from heptane. After filtration, 615 mg (86%) of a white powder are obtained. m.p.=182° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]([Cl:22])([Cl:21])[CH2:5][O:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8].S(OC)(O[CH3:27])(=O)=O.O>O1CCCC1>[CH3:27][N:9]([C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([O:6][CH2:5][C:4]([Cl:21])([Cl:22])[Cl:3])=[O:8]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cccc(NC(=O)OCC(Cl)(Cl)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(N(C)C(=O)OCC(Cl)(Cl)Cl)c1
Yield: 80.7 %

Procedure:
To a suspension of 0.14 g of 60% sodium hydride in 5 ml of tetrahydrofuran was dropwise added a solution of 1.0 g of ethyl 3-(2,2,2-trichloroethoxycarbonylamino)benzoate in 5 ml of tetrahydrofuran, and the resultant mixture was stirred at room temperature. Then, a solution of 0.45 g of dimethyl sulfate in 5 ml of tetrahydrofuran was dropwise added, and the resultant mixture was stirred at room temperature for 3 hours. After water was added to the mixture, the mixture was subjected to extraction with ethyl acetate, and an organic layer was washed twice with water and dried with anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane ethyl acetate=4:1) to obtain 0.84 g (yield 79%) of the title compound as an oily material.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH:24]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([O:27]C)=[O:26].[OH-].[Na+]>C1COCC1.CO.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH:24]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:25]([OH:27])=[O:26]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Yield: 92.4 %

Procedure:
A mixture of methyl 2-{[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}-3-phenylpropanoate (197 mg, 0.363 mmol), prepared in the previous step, and 1 N NaOH (544 μL, 0.544 mmol) in 20 mL of THF plus 20 mL of methanol plus 10 mL of water was refluxed under nitrogen for 3 h. The reaction was filtered, acidified by the addition of 2 mL of 1 N HCl and then concentrated under reduced pressure. The solid was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (178 mg, 92%) as a white solid, mp 220-224° C. Elemental Analysis for C28H20BrNO3S+0.18H2O Calc'd: C, 63.02; H, 3.85; N, 2.62. Found: C, 63.13; H, 3.70; N, 2.54.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)CC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)CC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-propionylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:38](COCC[Si](C)(C)C)[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]5[CH2:36][CH2:35]5)=[O:32])=[C:26]([Cl:37])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:38][C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]5[CH2:36][CH2:35]5)=[O:32])=[C:26]([Cl:37])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(OCc5ccccc5)cc4)cc23)cc1Cl)NC1CC1
Yield: 85.4 %

Procedure:
After dissolving 38 mg of 1-{4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}-3-cyclopropylurea in 0.8 ml of tetrahydrofuran, 0.2 ml of tetrabutylammonium fluoride (1 M tetrahydrofuran solution) was added dropwise and the mixture was refluxed for 2 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with ethyl acetate and tetrahydrofuran. The organic layer was washed with water and saturated brine, concentrated and dried under reduced pressure to obtain 26 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](N)=[O:5].N([O-])=[O:14].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:14])=[O:5]
Reactant: O=N[O-]
Reactant: Cc1cc(Cl)c(C(N)=O)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Cl)c(C(=O)O)c(Cl)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A stirred 0° C. solution of 2,6-dichloro-4-methylbenzamide (8.6 g, 42. mmol) in 2:1 (v/v) acetic acid-concentrated hydrochloric acid (165 ml) was treated dropwise with a solution of sodium nitrite (19.0 g, 275 mmol) in water (42 ml). The mixture was stirred 30 minutes at 5° C., slowly warmed to 85° C., and kept 1 hour. The mixture was cooled, concentrated under vacuum, and treated with cold water (50 ml). The product was filtered, washed twice with cold water, and dried 16 hours at 50° C. over phosphorus pentoxide under vacuum to provide 7.15 g (83%) of 2,6-dichloro-4-methylbenzoic acid, m.p. 139°-145° C.
Reaction SMILES: [Li].[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.[C:21]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>COCCOC.[Cl-].[Cl-].[Cl-].[Ti+3]>[C:21]1(=[C:7]([C:6]2[CH:19]=[CH:20][C:3]([F:2])=[CH:4][CH:5]=2)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCCC1
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(F)cc2)cc1
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(C(=C2CCCC2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
3.5 g (500 mmol) of lithium are added to a suspension of 25.4 g (165 mmol) of titanium trichloride in 300 ml of 1,2-dimethoxyethane. The mixture is refluxed for 2 hours and then cooled to room temperature. A solution of 7.5 g (27 mmol) of 4-fluoro-4'-methylsulfonylbenzophenone, prepared in Example 2, and 2.25 g (27 mmol) of cyclopentanone in 80 ml of 1,2-dimethoxyethane is added dropwise and the mixture is refluxed for 8 hours. After cooling, the mixture is treated with dilute hydrochloric acid solution and extracted with t-butyl methyl ether. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give a residue, which is chromatographed on silica gel in dichloromethane. The resulting oil crystallizes from an isopropyl ether/pentane mixture to give 4 g of 4-[(cyclopentylidene)(4-fluorophenyl)methyl]methylsulfonylbenzene in the form of crystals melting at 84°-85° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:27]([CH3:30])([O-:29])=[O:28]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:30]/[N+:27]([O-:29])=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: COCCOc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COCCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C

Procedure:
3-(Benzyloxy)-4-(2-methoxyethoxy)benzaldehyde described in Production Example 20-2 (17.6 g, 61.5 mmol) was dissolved in acetic acid (49.3 mL), then ammonium acetate (5.69 g, 73.8 mmol) and nitromethane (8.32 mL, 154 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated under reflux at 130° C. for 2 hours. The mixture was cooled to room temperature and then the precipitate was collected by filteration and washed with ethanol to quantitatively obtain the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:10]([CH:14]=1)[C:11](O)=[O:12]>C(O)C>[CH3:4][O:5][C:6]1[CH:14]=[C:10]2[C:9]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:2][NH:3][C:11]2=[O:12])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2n[nH]c(=O)c3cc(OC)ccc23)cc1
Yield: 89.7 %

Procedure:
18.5 mL (380 mmol) of hydrazine hydrate are added to a solution of 21.6 g (75 mmol) of 5-methoxy-2-(4-methoxybenzoyl)benzoic acid in 150 mL of ethanol and the mixture is refluxed for 2 hours. The reaction medium is cooled and then filtered. The precipitate obtained is washed with ethanol and then dried under reduced pressure at 40° C. 19 g of a white solid are obtained (90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([C@@H:57]([NH2:59])[CH3:58])=[N:56][C:52]=2[CH:51]=1.BrCl>O1CCCC1.ClCCl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:59][C@H:57]([C:55]1[NH:54][C:53]2[CH:60]=[CH:61][C:50]([Br:49])=[CH:51][C:52]=2[N:56]=1)[CH3:58])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Br)c1
Reactant: C[C@H](N)c1nc2cc(Br)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClBr
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Br)c1)c1nc2cc(Br)ccc2[nH]1
Yield: 72 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-bromo-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 72%; Rf value: 0.50 (silica gel: dichloromethane/ethanol=9:1); C21H18Br2N4O2 (518.207); mass spectrum: (M+H)+=517/519/521 (bromo-chlorine isotope).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[N:6][C:7]=1[CH3:8].[CH:16](OCC)=[O:17].[H-].[Na+]>C(COC)OC>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([CH:16]=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1cnc(C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1cnc(C)c(C)c1

Procedure:
Reaction of ethyl 3-(5,6-dimethyl-3-pyridyl)-propionate with ethyl formate and sodium hydride in dimethoxyethane at room temperature gave ethyl 3-(5,6-dimethyl-3-pyridyl)-2-formylpropionate, m.p. 148°-9°.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:21])[CH:15]=3)=[C:10]([CH3:22])[CH:9]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=3)=[C:10]([CH3:22])[CH:9]=2)[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CCC1(c2ccc(-c3cccc(C=O)c3)c(C)c2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC1(c2ccc(-c3cccc(CO)c3)c(C)c2)OCCO1

Procedure:
In a manner similar to that of Example 20(e), by reaction of 4.5 g (15.2 mmol) of 4′-(2-ethyl-[1,3]dioxolan-2-yl]-2′-methylbiphenyl-3-carbaldehyde with 760 mg (20 mmol) of lithium aluminium hydride, the desired product is obtained in the form of a colourless oil (m=4.4 g, Y=97%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[S:14][C:15]([C:22]([O-])=O)=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1>>[CH3:12][C:13]1[S:14][C:15]([C:22]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:7]=2)=[C:16]([C:18]([F:21])([F:19])[F:20])[N:17]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: Cc1nc(C(F)(F)F)c(C(=O)[O-])s1
Product: Cc1nc(C(F)(F)F)c(-c2nc(-c3ccc(Cl)cc3)no2)s1

Procedure:
The title compound was prepared from 4-chlorobenzamidoxime and 2-methyl-4-trifluoromethyl-thiazole-5-carboxylate similar to Example 16 as a light orange solid. 1H NMR (CDCl3): 8.08 (dd, J=8.52, 2.20 Hz, 1H), 7.50 (dd, J=8.51, 2.13 Hz, 1H), 2.85 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[CH3:14]I>O1CCCC1>[CH3:14][O:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1
Reactant: CI
Reactant: OCCSCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCSCc1ccncc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (170 mg., 7.1 mmoles, from 340 mg. of 50% dispersion in oil washed, under nitrogen, with hexane) was slurried in 5 ml. of dry tetrahydrofuran. A solution of 4-(2-hydroxyethylthiomethyl)pyridine (1.0 g., 5.9 mmoles) in 10 ml. was added dropwise over 5 minutes and the mixture stirred for 5 minutes. Finally, methyl iodide (260 mg., 0.1 ml., 5.9 mmoles) in 2 ml. of tetrahydrofuran was added and the mixture stirred overnight. The reaction mixture was clarified by filtration and evaporated to an oil (approximately 1.3 g.) which was chromatographed on silica gel with chloroform as eluent. Pure fractions of product were combined and concentrated to yield 4-(2-methoxyethylthiomethyl)pyridine [210 mg. of oil; m/e 183; pnmr/CDCl3 /TMS/delta: 7.4 (t, 2H), 6.7 (s, 3H), 6.5 (t, 2H), 6.3 (s, 2H), 2.7 (d, 2H), 1.4 (d, 2H)].
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.O1CCOCC1>ClCCl>[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2[N:23]=[CH:24][N:25]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)[C:21]=2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (15, 389.6 g, 0.765 mol) in dichloromethane (CH2Cl2, 7 L) was added a solution of hydrogen chloride (HCl) in dioxane (4 M, 1.15 L, 4.6 mol, 6.0 equiv) drop wise at room temperature. The resulting reaction mixture was stirred at room temperature for 48 h. When LCMS showed that all of the starting material had been consumed, the reaction mixture was transferred in portions to a 22 L separation funnel containing aqueous ammonium hydroxide (NH4OH, about 4% v/v, 2.5 L). Gas was evolved but the funnel stayed cool to the touch. Ice cubes were periodically added as a precaution. Once all of the reaction mixture was added, stirring was continued for about 15 min. The pH of the aqueous layer was found to be close to 11. The two layers were separated and the organic layer was washed with brine (2 L), dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure to a minimum volume. Heptane (about 3 L) was added to the residue and the resulting suspension was concentrated to dryness under reduced pressure to give crude 2-(3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (16, 268.2 g, 313.3 g theoretical, 85.6% yield) as an orange oil which was used directly for the subsequent reaction without further purification. For crude 16: 1H NMR (300 MHz, CDCl3): δ 8.92 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 7.47 (d, 1H), 6.87 (d, 1H), 5.74 (s, 2H), 4.36 (d, 2H), 3.95 (d, 2H), 3.77 (s, 2H), 3.62 (t, 2H), 1.9 (br. s, 1H), 0.99 (t, 2H), 0.01 (s, 9H) ppm; C20H27N7OSi (MW, 409.56), LCMS (EI) m/e 410 (M++H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)=[O:3].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.N1C=CC=CC=1>[N:20]1([C:2]([C:4]2[CH:19]=[CH:18][C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)=[CH:6][CH:5]=2)=[O:3])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
4-(4-Chlorocarbonylbenzyl)-nitrobenzene was dissolved in dichloromethane (40 mL) and a solution of pyrrolidine (64 mg, 1 eq) in pyridine (0.2 mL) was added. The mixture was stirred for 2 hours at room temperature, washed with dilute potassium hydroxide, and solvents evaporated to yield a yellow oil. The residue was chromatographed on silica gel, eluting with dichloromethane/methanol, to give 4-(4-pyrrolidin-1-ylcarbonylbenzyl)-nitrobenzene (299 mg, 99%).