Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[Li]CCCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.Cl>C1COCC1.C(OCC)(=O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([B:24]([OH:25])[OH:23])[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1cc(Br)c2c(c1)OCO2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1cc2c(c(B(O)O)c1)OCO2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a mixture of 4-bromo-6-isobutyl-benzo[1,3]dioxole (232 mg, 0.90 mmol) in THF (3 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.72 mL, 2.5 M, 1.80 mmol) dropwise. The reaction mixture was stirred for 5 minutes and triisopropylborate (0.62 mL, 2.71 mmol) was added dropwise. The mixture was stirred at −50° C. for 2 hours then warmed up to room temperature and stirred overnight at room temperature. 2.0 N HCl was slowly added to the reaction mixture. After 30 minutes the mixture was diluted with ethyl acetate and the layers separated. The organic layer was further washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (30% ethyl acetate in hexane) to give 110 mg of 6-isobutyl-benzo[1,3]dioxole-4-boronic acid (55%).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][C:13](=[O:25])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:15]=1[CH3:24]>ClCCl>[CH3:11][O:12][C:13](=[O:25])[C:14]1[C:15]([CH3:24])=[C:16]([O:22][CH3:23])[CH:17]=[C:18]([O:20][CH3:21])[C:19]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(OC)cc(OC)c1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(C)c(OC)cc(OC)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 340 ml of N,N-dimethylformamide in 1 l of dichloromethane were added slowly 404 ml of phosphoryl chloride. The solution was stirred for 1.5 h at room temperature, and then, a solution of 618 g of 3,5-dimethoxy-2-methylbenzoic acid methyl ester in 200 ml of dichloromethane was added within 10 min. The mixture was heated for 72 h at reflux temperature. After cooling, the mixture was slowly poured into 3 l of ice-water and subsequently extracted with 3.6 l of dichloromethane. The organic layer was washed with 2 l of saturated sodium carbonate solution and twice with 2 l of water. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The solid residue was triturated in 3 l of ethyl acetate at 60° C., and after cooling, 1.5 l of hexane were added. The solid was isolated by filtration to yield 646 g of 2-formyl-3,5-dimethoxy-6-methylbenzoic acid methyl ester, m.p. 164°-165° C.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][CH2:22][CH2:23][C:16]3=[CH:15][C:14]=2[C:13]=1[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[C:1]1([S:7]([NH:11][C:12]2[CH:20]=[CH:19][C:18]3[N:17]4[CH2:21][CH2:22][CH2:23][C:16]4=[CH:15][C:14]=3[C:13]=2[C:24]([O:26][CH3:27])=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(N)ccc2c1cc1n2CCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1cc1n2CCC1
Yield: 48.5 %

Procedure:
Benzenesulfonyl chloride (0.092 g) was added to a solution of methyl 7-amino-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 18, 0.100 g) in DCM (4 mL) and pyridine (1 mL) and the resultant mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and washed with aqueous potassium carbonate solution, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo, then dissolved in toluene and re-evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ammonia in methanol (2M) and DCM, with a gradient of 0-2%. The resultant solid was triturated with diethyl ether to give methyl 7-benzenesulfonylamino-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.078 g) as a cream powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[C:39]2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36][C:35]=2[C:34]([C:42]([OH:44])=[O:43])=[CH:33][CH:32]=1>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[C:39]4[C:38](=[O:40])[N:37]([CH3:41])[CH2:36][C:35]=4[C:34]([C:42]([OH:44])=[O:43])=[CH:33][CH:32]=3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CN1Cc2c(C(=O)O)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C(=O)O)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and Compound 128A. MS (ES+): m/z 624.19 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=O)[CH:12](Br)[CH2:11][CH2:10][C:9]=2[N:8](C(OC(C)(C)C)=O)[CH:7]=1)=[O:5])[CH3:2].[C:24]([NH2:27])(=[S:26])[CH3:25]>CO>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]3[N:27]=[C:24]([CH3:25])[S:26][C:12]=3[CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(N)=S
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CC2
Solvent: CO
Product: CCOC(=O)c1c[nH]c2c1-c1nc(C)sc1CC2
Yield: 34 %

Procedure:
To a mixture of 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid ethyl ester (2.4 mmol) in 10 mL 1,4-dioxane is added di-tert-butyl dicarbonate (2.9 mmol), followed by a solution of K2CO3 (2.9 mmol) in 5 mL H2O. After stirring at RT for 16 hours 50 mL ethyl acetate and 50 mL H2O are added to the mixture. The organic layer is separated and the aqueous layer is extracted several times with EtOAc. The organic layers are combined, dried over Na2SO4 and evaporated in vacuo yielding 4-Oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester, 700 mg, as a dark yellow/brown oil (95%). 1H NMR (CDCl3) 1.38 (t, 3H), 1.62 (s, 9H), 2.11-2.19 (m, 2H), 2.50-2.58 (m, 2H), 3.17 (t, 2H), 4.37 (q, 2H), 7.70 (s, 1H). Step 2: To the solution of 4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (33 mmol) in 140 mL THF is added dropwise a solution of phenyltrimethylammonium bromide (33 mmol) in 56 mL THF. After stirring at RT for an additional 1½ hours the mixture is poured onto 200 mL 5% NaHCO3 solution, and is then extracted several times with EtOAc. The organic layers are combined, dried over Na2SO4 and evaporated in vacuo. The dark brown oil is chromatographed using ethyl acetate 1: hexanes 10 as a mobile phase to yield 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester, 5 g, as a white solid (40%). 1H NMR (CDCl3)1.39 (t, 3H), 1.62 (s, 9H), 2.42-2.51 (m, 2H), 3.20-3.38 (m, 2H), 4.35 (q, 2H), 4.58 (t, 1H), 7.79 (s, 1H). Step 3: To a solution of 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (0.78 mmol) in 10 mL CH3OH is added thioacetamide (1.55 mmol). After stirring under refluxing for 16 hours the solvent is removed in vacuo. The brown oil is chromatographed using EtOAc 1: hexane 1, followed by 5% MeOH in CH2Cl2 as mobile phases to yield 2-methyl-5,6-dihydro-4H-thiazolo[4,5-e]indole-8-carboxylic acid ethyl ester as a white solid (34%). 1H NMR (DMSO-d6) 1.27 (t, 3H), 2.60 (s, 3H), 2.78 (t, 2H), 2.96 (t, 2H), 4.19 (q, 2H), 7.21 (s, 1H), 11.44 (s, 1H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[F:18][C:19]([F:34])([O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].[OH-].[Na+]>C(O)C(C)C>[F:18][C:19]([F:34])([O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]2[N:33]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:32]=2)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:21])[F:22]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CN(C)C=CC(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccncc3)n2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 13.2 g (75 mmol) of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one [described in EP-A-0 233 461] in 500 ml of isobutanol are added 23.6 g (75 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate. Following the addition of 4 g (100 mmol) of sodium hydroxide, the reaction mixture is stirred for 3 hours at 110° C. The suspension is concentrated under reduced pressure, the residue is dissolved in 500 ml of methylene chloride/tetrahydrofuran (1:1), and the solution is extracted with 300 ml of water. The organic phase is dried over sodium sulfate and concentrated on a rotovap. Recrystallisation from diethyl ether/tetrahydrofuran gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(4-pyridyl)-2-pyrimidine-amine; Rf =0.9 (methylene chloride:methanol =9:1), FAB-MS: 365 (M+ +1), m.p. 191°-192°.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:10](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH2:11]O)[CH2:6][CH2:7][CH2:8][CH3:9]>C(Cl)(Cl)Cl>[CH2:5]([C:10](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH2:11][Br:2])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: BrP(Br)Br
Reactant: CCCCCC(=Cc1ccc(Cl)cc1Cl)CO
Solvent: ClC(Cl)Cl
Product: CCCCCC(=Cc1ccc(Cl)cc1Cl)CBr
Temperature: 0 °C
Yield: 272.6 %

Procedure:
32.5 g of PBr3 were added dropwise to a solution of 93 g of (II) in 300 ml of CHCl3 at 10° C. The CHCl3 solution was stirred for 15 hours at room temperature and then poured into ice/water. The organic phase was separated off and the aqueous phase was extracted with CHCl3. The combined organic phases were washed several times with aqueous Na2CO3 solution and with water, dried over Na2SO4 and concentrated. Distillation of the residue gave 110 g of (III) of boiling point 140°-148° C./0.1 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@H:18]3O)[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:55]1(=[O:65])[NH:59][C:58](=[O:60])[C:57]2=[CH:61][CH:62]=[CH:63][CH:64]=[C:56]12>C1COCC1.C1COCC1.O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[N:59]3[C:55](=[O:65])[C:56]4[C:57](=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:58]3=[O:60])[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@@H](O)[C@H]4C3)c2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](N5C(=O)c6ccccc6C5=O)[C@H]4C3)c2n1
Reaction time: 12 h
Yield: 42 %

Procedure:
To a solution of (±)-(1S,5R,6R)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azabicyclo[3.2.0]heptan-6-ol (230 mg, 0.73 mmol) in THF (2 mL) as added DEAD (0.11 mL, 0.76 mmol), followed by dropwise addition of a preformed solution of PPh3 (190 mg, 0.72 mmol) and phthalimide-(107 mg, 0.73 mmol) in THF-dioxane (4 mL, 1:1). The resulting solution was heated at reflux. After 12 h, the solution was concentrated and the residue purified via a column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (137 mg, 42%) as a yellow oil: LC/MS (ES) m/e 448 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[C:33]2[C:28](=[N:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[N:27]([CH3:43])[C:26]1=[O:44]>>[CH3:24][N:25]1[C:33]2[C:28](=[N:29][CH:30]=[C:31]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:32]=2)[N:27]([CH3:43])[C:26]1=[O:44]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: Cn1c(=O)n(C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)n(C)c(=O)n5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1,3-dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Stage 67.1.1) to give the title compound as a white solid. (HPLC: tR 2.39 min (Method A); M+H=455 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.16-8.07 (m, 3H), 7.99-7.94 (m, 111, 7.58-7.53 (m, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 3.41 (s, 3H), 3.35 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])O.[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19](CO)[OH:20])[OH:18])[OH:16])[OH:14]>>[O:1]=[CH:2][CH2:3][C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6].[O:11]=[CH:12][C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=CC[C@H](O)[C@H](O)CO
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
It was surprising that the process of Niedballa and Vorbruggen formed the β-anomer to the near exclusion of the α-anomer only in the examples wherein deoxyribose and arabinose were utilized (DE 1 919 307, Examples 3 and 14). However, such results were not at all surprising where ribose or glucose was employed, because it is known that 2′-ester derivatives of ribose normally form the β-anomer in preference to the α-anomer product. Noteworthy is that where a predominance of β-anomeric product was formed from deoxyribose and/or arabinose as starting materials. Only low percent yields of product were obtained (DE 1 919 307 at Example 3, 20.5% yield from a deoxyribose starting material, and Example 14, 27.2% yield from an arabinose starting material).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:9]=1[CH3:10])=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:8]2[C:9]([CH3:10])=[C:5]([CH2:3][OH:2])[S:6][CH:7]=2)(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: COC(=O)c1scc(S(=O)(=O)c2ccc(Cl)cc2)c1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)csc1CO
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A solution of 4-(4-Chloro-benzenesulfonyl)-3-methyl-thiophene-2-carboxylic acid methyl ester (992 mg, 3.00 mmol) in dry tetrahydrofuran (20 mL) and dry CH2Cl2 (10 mL) was cooled to 0° C. under N2, and DIBAL-H (9.0 mL, 9.0 mmol, 1 M solution in toluene) was added. After 3 hours, another portion of DIBAL-H (4.5 mL, 4.5 mmol) was added, and stirring was continued for another 2 hours. The reaction was quenched by the addition of saturated Rochelle salt solution (30 mL), and the mixture was stirred for 1 hour at room temperature. The phases were separated, the aqueous phase was extracted with EtOAc (2×50 mL) and the pooled organic layers were dried over Na2SO4 and evaporated in vacuo. The product was purified by chromatography on silica gel on a FlashMaster system using as eluent heptane/ethyl acetate (linear gradient elution from 1:0 to 6:4). Fractions containing the product were pooled and evaporated in vacuo to yield the desired compound (788 mg, 87%). LC-MS: (m/z)=285.2 (M−H2O+H+), calcd for C12H10ClO2S2: 284.9805, tR=2.45 min. 1H NMR (CDCl3): 1.84 (t, J=5.7 Hz, 1 H), 2.20 (s, 3 H), 4.73 (d, J=5.7 Hz, 2 H), 7.49 (d, J=8.5 Hz, 2 H), 7.84 (d, J=8.5 Hz, 2 H), 8.18 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.O1CCCC1.C(OC([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=O)(C)(C)C.[Cl-].[NH4+]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([C:24]2[CH2:25][CH2:26][NH:21][CH2:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)s1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cl
Product: Clc1ccc(C2=CCNCC2)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
A 5-chlorothienyl magnesium bromide-tetrahydrofuran solution (Aldrich Co., 0.5 M, 22 ml) was cooled to 0° C., and 1-(tert-butoxycarbonyl)-4-piperidone (Aldrich Co. (hereafter the same), 2.0 g) was dissolved in tetrahydrofuran (10 ml) and added thereto. The mixture was heated under reflux for 8 hr. After completion of the reaction, the mixture was cooled to 0° C. A saturated aqueous ammonium chloride solution was added, and a solid was filtered off. The filtrate was extracted with diethyl ether. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate (5:1)). The intermediate was dissolved in ethyl acetate, and a 4N hydrochloric acid-ethyl acetate solution (3 ml) was added. The mixture was stirred at room temperature for 3 hr. After completion of the reaction, the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give 4-(5-chloro-2-thienyl)-1,2,3,6-tetrahydropyridine hydrochloride (637 mg, yield 23%).
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6](=[O:9])[S:7][CH:8]=1)(O)=[O:2].S(Cl)([Cl:12])=O>>[Cl:12][C:1]([C:4]1[NH:5][C:6](=[O:9])[S:7][CH:8]=1)=[O:2]
Reactant: O=C(O)c1csc(=O)[nH]1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1csc(=O)[nH]1

Procedure:
A mixture of 29 g of 4-carboxy-4-thiazoline-2-one [Enlenmeyer et al, Helv., Chim. Acta., Vol. 27 (1944), p.1432-6] and 200 ml of thionyl chloride was refluxed for 24 hours and was then cooled. The mixture was vacuum filtered to obtain 21 g of 4-chloroformyl-4-thiazoline-2-one melting at 184°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[CH:29][C:28]([NH2:31])=[N:27][C:25]=4[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:34]([N:41]1[CH:45]=[CH:44]N=C1)(N1C=CN=C1)=[O:35].[CH:46]1(N)[CH2:50]CC[CH2:47]1>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[CH:29][C:28]([NH:31][C:34]([NH:41][CH:45]5[CH2:44][CH2:50][CH2:46][CH2:47]5)=[O:35])=[N:27][C:25]=4[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4ccc(N)nc4n3)cc2)CC1
Reactant: NC1CCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4ccc(NC(=O)NC5CCCC5)nc4n3)cc2)CC1
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
To a solution of 0.150 g (0.36 mmol) of 4-[4-(7-amino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (Example 13) in 2 mL of dimethylformamide, cooled in an ice bath, is added 0.022 g (0.54 mmol) of 60% sodium hydride. The cooled solution is stirred for 15 minutes, then treated with 0.088 g (0.54 mmol) of carbonyldiimidazole. The cooled solution is stirred for another 30 minutes, then treated with 0.071 mL (0.72 mmol) of cyclopentylamine. The resulting solution is stirred at room temperature for 1 hour, then added to cold water. The solid is collected by filtration to give a first crop of material. The aqueous filtrate is then extracted with dichloromethane, and the extracts are dried (magnesium sulfate) and concentrated to give a second crop of material. The 2 crops are combined and purified by flash chromatography, eluting with a gradient of 0% to 5% methanol/dichloromethane during 30 minutes to give 0.1159 g (60.4%) of the product as a solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O[CH:8]=[C:9]([C:12](=[O:23])[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=1[F:22])[C:10]#[N:11])C>C(Cl)(Cl)Cl.C(O)C.CCCCCC>[CH:1]1([NH:4][CH:8]=[C:9]([C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])[C:10]#[N:11])[CH2:3][CH2:2]1
Reactant: CCOC=C(C#N)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: NC1CC1
Solvent: CCO
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: N#CC(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A solution of cyclopropylamine (3.3 g) in chloroform (20 ml) is added dropwise to a solution of 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile (14.0 g) in chloroform (50 ml) with maintaining the internal temperature between 6° C. and 8° C. by using an ice bath. The mixture is allowed to stand overnight at room temperature and then concentrated under vacuum to yield an orange oily residue. The oily residue is dissolved in ethanol and the ethanol is removed in vacuum to afford a crystalline residue. The residue is dissolved in hexane and washed with a 20:1 mixture of hexane and ethanol to yield 3-cyclopropylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile (12.6 g) as pale yellow prisms, m.p. 88°-89° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH:13]1([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C[OH:36]>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([N:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:20]([NH:19][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:36])=[O:8])([O-:3])=[O:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CO
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)N(C(=O)c1ccccc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A solution of 25 g (0.15 mol) of 2-nitro-benzoic acid in 75 ml of methanol was added dropwise to a boiling solution of 31 g (0.15 mol) of dicyclohexyl-carbodiimide and 8 ml of triethylamine in 300 ml of methanol. The reaction mixture was heated under reflux for 2 hours and stirred at room temperature overnight. After distilling off the solvent in vacuo, the residue was recrystallized from isopropanol. 25 g (45% of theory) of N-(2-nitrobenzoyl)-N,N'-dicyclohexyl-urea of melting point 134° C. were obtained.