Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.C([O:5][C:6]([C@@H:8]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=[O:30])[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[S:22][CH2:21]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:7])C.C(O)(=O)C>[OH-].[Na+]>[C:6]([C@@H:8]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=[O:30])[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[S:22][CH2:21]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
In 10 ml of 1N aqueous sodium hydroxide solution is dissolved 0.45 g of 3(R)-[1(S)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrobromide, and the solution is allowed to stand at room temperature for 30 minutes. The reaction solution is neutralized with 2 ml of acetic acid and purified by MCI gel column chromatography (water:methanol=2:1). The eluent is concentrated under reduced pressure and the residue is lyophilized to give 0.3 g of 3(R)-[1(S)-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a solution of 5-(4-Chloro-phenyl)-thiophene-2-carbaldehyde (5 g, 22.45 mmol) in methanol (250 ml) at 0° C. under an atmosphere of nitrogen was added sodium borohydride (1.02 g, 26.94 mmol) portionwise over a period of 5 minutes. The reaction was then allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (100 ml) and stirred for 5 minutes, before the methanol is removed under reduced pressure. The resulting heterogeneous mixture was then extracted with ethyl acetate (2×100 ml), the combined organics dried over magnesium sulphate and the solvent removed under reduced pressure to give [5-(4-Chloro-phenyl)-thiophen-2-yl]-methanol (4.89 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH2:14][CH3:15])[N:5]=[C:4]([NH:16][CH3:17])[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])#[N:19].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH2:14]([C@@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[N:5]=[C:4]([NH:16][CH3:17])[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([F:29])[CH:22]=2)[CH:7]=1)[CH3:15]
Reactant: CC[C@@H]1COCCN1c1cc(Cl)nc(NC)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@@H]1COCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(NC)n1
Temperature: 140 °C
Yield: 139.5 %

Procedure:
4-Chloro-6-[(3R)-3-ethyl-4-morpholinyl]-N-methyl-2-pyrimidinamine (250 mg, 0.974 mmol) was added to a 20 mL microwave vial, followed by (4-cyano-3-fluorophenyl)boronic acid (209 mg, 1.266 mmol), PdCl2(dppf).CH2Cl2 adduct (39.8 mg, 0.049 mmol), 2M K2CO3 (1.461 mL, 2.92 mmol) and 1,4-dioxane (4 mL). The mixture was heated to 140° C. for 10 minutes. The reaction mixture was filtered through a silica plug and washed with EtOAc (3×). The filtrate was then washed with H2O (2×) and the organic layer was dried over Na2SO4 and concentrated to afford the title compound (464 mg) as a brown oil. LC-MS (ES) m/z=342 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:21][CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([O:22][CH:23]4[CH2:28][CH2:27][C:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:29])[CH2:25][CH2:24]4)[C:12]=3[C:11]1=2)(C(C)(C)C)(C)C>O1CCCC1>[OH:8][CH2:9][C@H:10]1[CH2:21][CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([O:22][CH:23]4[CH2:24][CH2:25][C:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:29])[CH2:27][CH2:28]4)[C:12]=3[C:11]1=2
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CO[Si](C)(C)C(C)(C)C)CC4)CC1
Solvent: C1CCOC1
Product: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a solution of tert-butyl N-(4-[[(3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (1.20 g, 2.19 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was added TBAF-3H2O (1.09 g, 3.45 mmol, 1.58 equiv) at 0° C. and the resulting solution was stirred for 3 h at room temperature. The reaction was quenched with water and extracted with 3×100 mL of ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification by column chromatography on silica gel with ethyl acetate/petroleum ether (1:20 to 1:5) afforded tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (900 mg, 95%) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[CH2:25]([CH:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:32]O)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[I:42]I>ClCCl>[I:42][CH2:32][CH:31]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCC(CO)CCCCCC
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCC(CI)CCCCCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
Under air, triphenylphosphine (107.44 g, 410 mmol, 1.19 equiv.) and imidazole (28.9 g, 424 mmol, 1.23 equiv.) were dissolved in dichloromethane (800 mL). 2-Hexyl-1-decanol (100 mL, 345 mmol., 1.00 equiv.) was added to the solution, and the reaction mixture was cooled to 0° C. Iodine (103.6 g, 408 mmol., 1.18 equiv.) was added portion-wise over 1 hour, after which the suspension was stirred at 0° C. for an additional hour, and then at ambient temperature for 18 hours. The mixture was quenched with saturated aqueous Na2SO3 (150 mL), and DCM was removed in vacuo. Hexane (200 mL) was added to the residue, and the mixture was filtered to remove salts that had precipitated. The organic material was extracted with hexanes (3×300 mL), dried over Na2SO4, filtered through a pad of silica gel, and then concentrated in vacuo to give a clear, colorless oil (97.8 g, 82% yield). 1H NMR (500 MHz, CDCl3) δ 3.28 (d, J=4.6 Hz, 2H), 1.34-1.19 (m, 24H), 1.12 (b, 1H), 0.91-0.87 (m, 6H).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([O:12][CH2:13][C:14]([O:16]CC)=O)=[CH:10][CH:9]=[CH:8]N=1)=O)C.[O-]CC.[Na+]>C1(C)C=CC=CC=1>[O:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:4][C:6]=2[C:14](=[O:16])[CH2:13]1
Reactant: CCOC(=O)COc1cccnc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1COc2ccccc21
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To a stirred solution of 1.0 g (4.2 mmol) of the title compound from Step B in 30 ml toluene was added 2.9 g (9.2 mmol) of 21% sodium ethoxide. The reaction was refluxed overnight. After cooling down to RT, the reaction was filtered and the solid was collected. The solid was then dissolved in 20 ml water, and acidified by acetic acid. The solid was filtered and washed with dichloromethane and dried. The solid was added to 30 ml of 10% HCl aqueous solution and refluxed for 3 hr. Then HCl was evaporated to give 350 mg (62% yield) of the title compound. LC/MS: (M+1) 136.1
Reaction SMILES: [Br:1][CH:2]1[CH:8]([OH:9])[CH2:7][CH:6]2[CH:3]1[CH2:4][C:5]2=[O:10].[CH3:11][CH:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>[Br:1][CH:2]1[CH:8]([O:9][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:11])[CH2:7][CH:6]2[CH:3]1[CH2:4][C:5]2=[O:10]
Reactant: O=C1CC2C1CC(O)C2Br
Reactant: CC(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(OC1CC2C(=O)CC2C1Br)c1ccccc1
Yield: 128.7 %

Procedure:
A mixture of 2-bromo-3-hydroxybicyclo[3.2.0]heptan-6-one (15 g), α-methylbenzyl alcohol (36 g) and p-toluenesulphonic acid (1 g) was heated at 90° for 6 h. The solution was poured into 8% sodium bicarbonate (300 ml) and extracted with ether (4×150 ml). The combined extracts were washed with brine (300 ml), dried (MgSO4) and evaporated to afford crude 2-bromo-3-(1-phenylethoxy)bicyclo[3.2.0]heptan-6-one as a pale yellow oil (29.1 g). The crude product (28.1 g) was dissolved in acetone (50 ml) and treated with morpholine (19 ml). The mixture was stirred for 3 h, poured into water (200 ml) and extracted with ether (4×150 ml). The combined extracts were washed with brine (200 ml), dried (MgSO4) and evaporated. The product was purified by chromatography on silica eluting with ether-petroleum ether (7:3) to give the title compound as a waxy solid (15.7 g). I.R. (CHBr3) 1745 cm-1.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][CH:22]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N-]=C=O>CN(C=O)C.C(O)(=O)C>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[C:36]([N:24]1[CH2:25][CH:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:22]([CH2:21][N:13]([CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]1)=[O:37]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(c1cccc2ccccc12)N(CC1CN(C(=O)c2ccccc2Cl)CC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
A mixture of 9.9 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[4-phenylpyrrolidin-3-yl]methyl}carbamate, 4.9 mg of 2-chlorobenzaldehyde, 50 μl of acetic acid and 0.5 ml of DMF was mixed at room temperature with 75 mg of MP-Triacetoxyborohydride (mfd. by Argonaut Technologies, USA) and stirred for 15 hours. At room temperature, the reaction solution was mixed with 50 mg of PS-Isocyanate (mfd. by Argonaut Technologies, USA) and stirred for 4 hours, and the reaction solution was filtered. The filtrate was concentrated under a reduced pressure to obtain tert-butyl {[1-(2-chlorobenzoyl)-4-phenylpyrrolidin-3-yl]methyl}[1-(1-naphthyl)ethyl]carbamate as a crude product. A 0.5 ml methanol solution of the thus obtained crude product was mixed with 0.5 ml of 4 M hydrogen chloride/ethyl acetate solution at room temperature and stirred for 4 hours. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a fractional high performance liquid chromatography (methanol-0.1% formic acid aqueous solution) to obtain 3.3 mg of N-{[1-(2-chlorobenzoyl)-4-phenylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20]>>[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: CC(C)N1CCNCC1
Product: COc1cc(N2CCC(N3CCN(C(C)C)CC3)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18) and 1-isopropylpiperazine. m/z 363.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:15][CH2:14][N:13](C#N)[CH2:12][CH2:11]2)=[N:2]1.[OH-].[Na+]>OS(O)(=O)=O>[N:10]1([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: N#CN1CCN(c2n[nH]c3ccccc23)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Yield: 73 %

Procedure:
A mixture of 4-(1 H-indazol-3-yl)-1-piperazinecarbonitrile (8.0 g, 40 mmol) and 25% H2SO4 (100 ml) was stirred at reflux for 4.5 hours. The reaction was cooled in an ice bath and made basic by the dropwise addition of 50% NaOH. The basic solution was extracted with ethyl acetate. The ethyl acetate was washed with H2O, dried with MgSO4, and concentrated to afford 5.2 g (73% of the desired compound, as a solid. The solid was recrystallized twice from toluene to afford 3.0 g of 3-(1-piperazinyl)-1 H-indazole, m.p.=153°-155° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C@H:19]([CH3:28])[CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:29]([C:32]1[N:33]=[N:34][N:35]([CH2:37][C:38](O)=[O:39])[CH:36]=1)([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>>[CH3:28][C@@H:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][N:35]3[CH:36]=[C:32]([CH:29]([CH3:30])[CH3:31])[N:33]=[N:34]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)[CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1
Reactant: CC(C)c1cn(CC(=O)O)nn1
Reactant: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cn(CC(=O)Nc2cncc(C(=O)c3cn([C@H](C)COC4CCCCO4)c4ncncc34)c2)nn1

Procedure:
Prepared according to the method described above for Example 1, using (5-aminopyridin-3-yl){7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Preparation 36) and (4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid with DIPEA as base.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]([O:9][C:10]([NH:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=[O:11])([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[CH:6]([O:9][C:10]([NH:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:3](=[O:4])[CH2:2][Br:1])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=[O:11])([CH3:8])[CH3:7]
Reactant: CC(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Br)CBr
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)Nc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1

Procedure:
Bromoacetyl bromide (18.6 g) was added dropwise with stirring to a solution of 4-isopropoxycarbonylamino-2-nitroaniline (22g) in toluene (300 ml). The solution was refluxed for 1 hour, cooled, and the solid filtered off and recrystallised from benzene to give N-(4-isopropoxycarbonylamino-2-nitrophenyl)-2-bromoacetamide (20 g), m.p. 195°-197° C.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OCC)=O)[C@@H:6]([CH3:16])[CH2:5]1)[CH:2]=[CH2:3].[OH-].[K+].C(=O)=O.C1(C)C=CC=CC=1>C(O)C>[CH2:1]([N:4]1[CH2:5][CH:6]([CH3:16])[NH:7][CH2:8][CH:9]1[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N(C(=O)OCC)C[C@H]1C
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=CCN1CC(C)NCC1C
Temperature: 100 °C

Procedure:
Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78 mol) was added to a solution of 87% potassium hydroxide pellets (2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5 hours. Carbon dioxide evolution was observed for the first 0.5-1 hour of heating. The reaction was cooled below reflux temperature and 2000 mL of toluene was carefully added. Ethanol was removed by azeotropic distillation at 105° C., while adding an additional 4000 mL of toluene to the reaction flask during the course of the distillation. After collection of 9000 mL of distillate, the reaction was cooled to 100° C. and 1000 mL of toluene was carefully added. The solution was slowly cooled to 5° C. and maintained at 5° C. for 30 minutes. The solution was filtered, and the filter cake was washed with an additional 1500 mL of toluene. The filtrate was washed with 1000 mL of water, dried over magnesium sulfate, and the solvent was removed to give 296 g (69%) of trans, 1-allyl-2,5-dimethylpiperazine as a dark liquid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[CH3:42][N:43]1[C:47]2[N:48]=[C:49]([C:70]#[N:71])[N:50]=[C:51]([C:52]3[CH:53]=[N:54][C:55]([O:62][CH2:63][CH:64]4[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]4)=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=3)[C:46]=2[CH:45]=[CH:44]1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[C:70]([C:49]1[N:50]=[C:51]([C:52]2[CH:57]=[C:56]([C:58]([F:59])([F:60])[F:61])[C:55]([O:62][CH2:63][CH:64]3[CH2:69][CH2:68][N:67]([C:38]([CH:35]4[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:37][CH2:36]4)=[O:40])[CH2:66][CH2:65]3)=[N:54][CH:53]=2)[C:46]2[CH:45]=[CH:44][N:43]([CH3:42])[C:47]=2[N:48]=1)#[N:71]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Cn1ccc2c(-c3cnc(OCC4CCNCC4)c(C(F)(F)F)c3)nc(C#N)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1ccc2c(-c3cnc(OCC4CCN(C(=O)C5CCN(C(=O)OC(C)(C)C)CC5)CC4)c(C(F)(F)F)c3)nc(C#N)nc21
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (546 mg) was added to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (329 mg) in DMF (10 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. 7-Methyl-4-[6-(piperidin-4-yl methoxy)-5-(trifluoromethyl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (500 mg) and N,N-diisopropylethylamine (0.38 mL) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature overnight. After EtOAc and a saturated aqueous NaHCO3 solution were added to the reaction mixture, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=100:0 to 96:4), whereby tert-butyl 4-{[4-({[5-(2-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-yl]oxy}methyl)piperidin-1-yl]carbonyl}piperidine-1-carboxylate (488 mg) was obtained as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[S:13][C:14]([Br:17])=[CH:15][CH:16]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl>C1COCC1>[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][N:8]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])[S:9]([C:12]1[S:13][C:14]([Br:17])=[CH:15][CH:16]=1)(=[O:10])=[O:11]
Reactant: COCCOCCl
Reactant: Cc1noc(NS(=O)(=O)c2ccc(Br)s2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
N-(3,4-Dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (680 mg, 2 mmol) in dry THF (2 mL) was added to sodium hydride (121 mg of a 60% oil dispersion, 3 mmol) in dry THF (1 mL). The resulting suspension was cooled to 0° C. and methoxyethoxymethyl chloride (334 mg, 2.68 mmol) was added dropwise via syringe. The solution was warmed to room temperature, and stirring continued overnight. Evaporation of solvent left an oil that was extracted into ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated. Flash chromatography of the residue on silica gel using 10-15% ethyl acetate/hexanes yielded 480 mg (56%) of a colorless oil.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([S:46][CH3:47])=[CH:42][CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([S:46][CH3:47])=[CH:42][CH:41]=2)\[C:20]2[CH:21]=[CH:22][C:17]([C:3]#[C:2][CH2:1][N:4]3[CH:8]=[CH:7][CH:6]=[N:5]3)=[CH:18][CH:19]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC)cc2)cc1C
Reactant: C#CCn1cccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCn3cccn3)cc2)c2ccc(SC)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpyrazole (0.530 g, 5.0 mmol) and diisopropylamine (1.6 mL, 11.7 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-methylsulfanylphenyl)allyloxy]-2-methylphenoxy]acetate (1.40 g, 2.5 mmol; prepared as described in example 40) in tetrahydrofuran (35 mL). The mixture was degassed and copper(I) iodide (38.0 mg, 0.2 mmol) and bis(triphenylphosphine)palladium(II) dichloride (87.5 mg, 0.12 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[2-methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-phenoxy]acetate as yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:21]([C:2]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nc2ccccc2c2[nH]cnc12
Reactant: Oc1ccccc1
Product: c1ccc(Oc2nc3ccccc3c3[nH]cnc23)cc1

Procedure:
In step (4) of Reaction Scheme IV a 4-chloro-1H-imidazo[4,5-c]quinoline of Formula XX is reacted with phenol to provide a 4-phenoxy-1H-imidazo[4,5-c]quinoline of Formula XXI. The phenol is reacted with sodium hydride in a suitable solvent such as diglyme to form a phenoxide. The phenoxide is then reacted at an elevated temperature with a compound of Formula XX.