Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][CH2:12][CH2:13][C:14]1[C:19](=[O:20])[N:18]2[CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[C:17]2=[N:16][C:15]=1[CH3:26].C(N(CC)CC)C>ClCCl>[Cl:11][CH2:12][CH2:13][C:14]1[C:19](=[O:20])[N:18]2[CH2:21][CH2:22][CH2:23][C:24](=[O:25])[C:17]2=[N:16][C:15]=1[CH3:26]
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2n(c(=O)c1CCCl)CCCC2=O
Reaction time: 0.5 h

Procedure:
A solution of oxalylchloride (8.8 ml) in dichloromethane (20 ml) was cooled to −65° C. and a solution of dimethyl sulfoxide (6.5 ml) dissolved in dichloromethane (20 ml) was added to it slowly and stirred for 30 min. keeping the temperature at −65° C. a solution of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (5 grams) (formula-7) dissolved in dichloromethane (30 ml) was added to it very slowly and stirred for 40 min. Triethyl amine was added to the reaction mixture and then quenched with water. The organic layer was separated, washed with aqueous sodium carbonate and water. The solvent from the organic layer was distilled off under reduced pressure to provide the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([I:18])[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[I:18][C:4]1[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[C:2]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: C1CCNC1
Reactant: Nc1ccc(S(=O)(=O)c2cc(I)nc(I)c2)cc1
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)c2cc(I)nc(N3CCCC3)c2)cc1
Yield: 75 %

Procedure:
0.127 g (0.000261 Mol) 4-(2,6-Diiodo-pyridine-4-sulfonyl)-phenylamine were dissolved in dioxane (5 ml) and treated with 0.22 ml (0.0026 Mol) pyrrolidine for 6 h at ambiente temperature. Then the solvent was removed, the residue dissolved in ethyl acetate, washed with 1N HCl, sat. bicarbonate and brine, dried over MgSO4 and evaporated. After chromatography on SiO2 with ethyl acetate hexane 1:2 and drying in a high vacuum it was obtained 0.084 g (75%) of 4-(2-iodo-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine as a beige solid; mp.: 218-221° C. (dec.).
Reaction SMILES: [F:1][CH:2]1[C:7]([F:9])([F:8])[C:6]2([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:11][C:3]1([OH:15])[CH2:4][CH2:5]2.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[C:20]([F:27])[C:19]=1[F:28].[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][O:15][C:3]23[CH2:11][CH2:10][C:6]([CH2:12][CH2:13][CH3:14])([CH2:5][CH2:4]2)[C:7]([F:8])([F:9])[CH:2]3[F:1])=[C:19]([F:28])[C:20]=1[F:27])[CH3:26]
Reactant: CCOc1ccc(CBr)c(F)c1F
Reactant: CCCC12CCC(O)(CC1)C(F)C2(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCC12CCC(OCc3ccc(OCC)c(F)c3F)(CC1)C(F)C2(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2,3,3-Trifluoro-1-hydroxy-4-n-propylbicyclo[2.2.2]octane (4) (37.5 mg), and 4-bromomethyl-1-ethoxy-2,3-difluorobenzene (5) (65.4 mg) were added to a dimethyl formamide suspension (2.0 mL) of sodium hydride (4.9 mg), the mixture was stirred at room temperature for 2.5 hours, and then added with saturated aqueous ammonium chloride solution to thereby terminate the reaction. The organic layer was extracted three times with ethyl acetate, the organic layers were combined, and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then vaporized off under reduced pressure, to thereby obtain a crude product. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9:1), to thereby obtain 1-(4′-ethoxy-2′,3′-difluorophenyl)methyloxy-2,3,3-trifluoro-4-n-propyl bicyclo[2.2.2]octane (6) (yield=39.9 mg, yield ratio=60%) as a colorless clear crystal.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:25][C:24]4[C:23]([F:22])=[CH:30][C:29]([F:31])=[CH:28][C:27]=4[F:32])[CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: Nc1nc(N2CCNCC2)cn2nc(-c3ccco3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(N2CCN(Cc3c(F)cc(F)cc3F)CC2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 2-furan-2-yl-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine in methylene chloride (see Example 16 above) was added 2,4,6-trifluorobenzaldehyde (28 mg, 0.18 mmol), sodium triacetoxyborohydride (46 mg, 0.22 mmol) and acetic acid (6 μL, 0.1 mmol). The reaction was stirred at room temperature for overnight. After the solvent was removed, the residue was subjected to flash chromatography (ethyl acetate/hexanes=30:70, 40:60) to afford 2-furan-2-yl-6-[4-(2,4,6-trifluoro-benzyl)-piperazin-1-yl]-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as a white solid (35 mg, 56%). 1H NMR (300 MHz, CDCl3) δ2.66 (t, J=4.5 Hz, 4H), 3.34 (t, J=4.5 Hz, 4H), 3.73 (s, 2H),5.61 (s, 2H), 6.54 (dd, J=1.8, 3.6 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 7.07 (d, J=3.6 Hz, 1H), 7.26 (s, 1H), 7.57 (d, J=1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ46.53, 48.35, 51.56, 95.63, 99.82, 100.10, 100.38, 110.29, 111.73, 134.80, 143.80, 146.00, 146.42, 149.06, 155.13.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:27]([NH:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:27]([NH:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][N:23]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCNC1
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCN(S(C)(=O)=O)C1

Procedure:
3-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylpiperidine-3-carboxamide (Example 90.1, Isomer 2) was coupled with methanesulfonyl chloride using an analogous method to that described for the equivalent step in Example 89 to give (S or R)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methyl-1-(methylsulfonyl)piperidine-3-carboxamide (Example 90, Isomer 2); 1H NMR Spectrum: (DMSO d6) 1.67 (m, 1H); 1.92 (m, 2H); 2.07 (m, 1H); 2.21 (s, 3H); 2.66 (d, 3H); 2.88 (s, 3H); 3.03 (m, 1H); 3.21 (m, 1H); 3.34 (d, 1H); 3.52 (d, 1H); 3.62 (d, 1H); 3.79 (d, 1H); 3.96 (s, 3H); 7.20 (s, 1H); 7.30 (dt, 1H); 7.50 (m, 1H); 7.62 (m, 2H); 8.32 (s, 1H); 8.44 (s, 1H); 9.57 (s, 1H); Mass Spectrum: (M+H)+ 565.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH:4]([Br:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(OC)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(OC)c1

Procedure:
To a solution of (3-methoxy-phenyl)-acetic acid methyl ester (19.6 mmol) in CCl4 was added N-bromosuccinimide (19.6 mmol) and the reaction mixture was irradiated for 2 hours. The reaction mixture was then concentrated in vacuo to afford the intermediate bromo-(3-methoxy-phenyl)-acetic acid methyl ester. To a solution of bromo-(3-methoxy-phenyl)-acetic acid methyl ester in THF (30 mL) under an atmosphere of nitrogen was added a solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (20.6 mmol) in THF (20 mL) followed by K2CO3 (39.2 mmol, 2 equivalents). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was partitioned between water (50 mL) and EtOAc (2×50 mL), the combined organics were dried (sodium sulfate) and concentrated in vacuo to afford an oil. The oil was purified by silica gel column chromatography using as eluent EtOAc:petrol (1:1) to give the title compound as an oil in 53% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2].[NH2:16][C:17]1[S:18][CH2:19][C:20](=[O:22])[N:21]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:16][C:17]1[S:18]/[C:19](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][CH:5]=[C:4]3[O:3][CH2:1][CH3:2])/[C:20](=[O:22])[N:21]=1
Reactant: CCOc1ccnc2ccc(C=O)cc12
Reactant: NC1=NC(=O)CS1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1ccnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 34 was used, starting with 4-ethoxy-quinoline-6-carbaldehyde (example 3b), 2-amino-thiazol-4-one, sodium acetate and acetic acid to give 2-Amino-5-[1-(4-ethoxy-quinolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 300 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(OCC)(=O)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1ccc(N)c(Oc2ccccc2Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cc2Oc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of 4-amino-3-(2-bromophenoxy)-benzonitrile, 2a (0.8 g; 2.77 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.1 g; 5.52 mmol) in dichloroethane (80 mL) was added sodium triacetoxyborohydride (1.17 g; 5.52 mmol) and acetic acid (0.16 mL; 2.8 mmol). The mixture was stirred for 2 h at rt. An additional 4 equiv of sodium triacetoxyborohydride was added, and the mixture was heated to 90° C. for 5 h. The mixture was allowed to cool to rt, diluted with ethyl acetate (15 mL) and treated with H2O (15 mL). The organic layer was separated, dried over MgSO4, filtered, and evaporated. The residue was purified via column chromatography (eluent gradient: 0 to 30% ethyl acetate in heptane) to yield 0.6 g (46%) of 4-[2-(2-bromophenoxy)-4-cyanophenylamino]-piperidine-1-carboxylic acid tert-butyl ester, 3a. MS m/z (MH+) 493.7.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C@@:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:33]5[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@]1(C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC[C@]1(C)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Temperature: 140 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
The compound (105 mg, 0.23 mmol) obtained in Example 3-2), 3-pyridylboronic acid (31 mg, 0.25 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.01 mmol), tricyclohexylphosphine (8 mg, 0.03 mmol), and tripotassium phosphate (84 mg, 0.38 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (1 mL), and the mixture was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, then diluted with methylene chloride (20 mL), and separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (10 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 30%) to obtain a partially purified product (110 mg) of the title compound in a light yellow solid form.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].CCO.CCO.CCO.CCO.[Ti:20]>>[CH3:6]/[C:5](/[OH:7])=[CH:4]/[C:1]([CH3:2])=[O:3].[CH3:6]/[C:5](/[OH:7])=[CH:4]/[C:1]([CH3:2])=[O:3].[CH3:6]/[C:5](/[OH:7])=[CH:4]/[C:1]([CH3:2])=[O:3].[CH3:6]/[C:5](/[OH:7])=[CH:4]/[C:1]([CH3:2])=[O:3].[Ti:20]
Reactant: CC(=O)CC(C)=O
Agent: [Ti]
Solvent: CCO
Product: CC(=O)/C=C(/C)O

Procedure:
1 g of acetylacetone and 1 g of tetraethyl orthotitanate were added to the hydrophilic sol-gel liquid to prepare it,
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[Cl:13]N1C(=O)CCC1=O>CN(C)C=O>[Cl:13][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[F:9]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(Cl)c(F)c1F
Temperature: 85 °C

Procedure:
2,3-Difluoro-6-nitroaniline (15.4 g, 88.7 mmol), N-chlorosuccinimide (14.9 g, 111.4 mmol) and N,N-dimethylformamide (250 mL) were combined and were heated to 80-90° C. for several hours, after which time the mixture was poured into ice water. The product was extracted with ethyl acetate which was then washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the solvents were removed in vacuo to leave a yellow, viscous oil. 1H NMR (DMSO-d6) δ: 8.03 (dd, J=7.3, 2.2 Hz, 1H, Ar—H), 7.65 (br s, 2H, NH2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:20]=1.N#N.C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]([C:7]2[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=2[CH3:1])[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])[CH2:29][CH2:30][CH3:31]
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCCCOc1cc(Br)ccc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: N#N
Solvent: C1COCCO1
Product: CCCCOc1cc(-c2ccc(O)cc2C)ccc1C=O
Temperature: 90 °C
Yield: 85.2 %

Procedure:
A solution of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.210 g, 0.898 mmol) and 4-bromo-2-butoxy-benzaldehyde (0.210 g, 0.817 mmol) in 1,4-dioxane (20 mL) is evacuated and re-filled with N2 3 times. To this solution, Pd(PPh3)4 (0.010 g) and aqueous Na2CO3 (1.0 mL, 2.0 M) are added. The resulting mixture is heated at 90° C. for 24 hours under N2. The reaction mixture is cooled to room temperature, neutralized with HCl (1.0 M, 3.0 mL), and concentrated. The residue is extracted with ethyl acetate (30 mL×2), and the combined organic layers are dried over sodium sulfate and concentrated. The residue is purified via silica gel chromatography eluting with 25-30% ethyl acetate in hexanes to give the title compound (0.198 g, 85%). ES/MS m/e 283.0 (M−1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7]O.[C:9]1([NH:15][C:16]2([C:22](=[O:25])[CH2:23][CH3:24])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[C:9]1([NH:15][C:16]2([C:22](=[O:25])[CH2:23][CH3:24])[CH2:21][CH2:20][N:19]([CH2:7][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCc1cccs1
Reactant: CCC(=O)C1(Nc2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCC(=O)C1(Nc2ccccc2)CCN(CCc2cccs2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4.1 parts of 2-thiopheneethanol, methanesulfonate ester, 3.5 parts of 1-[4-(phenylamino)-4-piperidinyl]-1-propanone, 5.3 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed for 18 hours. After cooling to room temperature, the reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-{4-(phenylamino)-1-[2-(2-thienyl)ethyl]-4-piperidinyl}-1-propanone; mp. 127.1° C.
Reaction SMILES: [CH3:1][C@@H:2]1[N:10]([C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)[CH2:9][C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([C:24](OC(C)(C)C)=O)[CH2:3]1.ClC1[N:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([F:42])[CH:38]=2)[N:33]=1.C(N(CC)CC)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.CN(C=O)C.CCOC(C)=O>[F:42][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:24]([N:4]1[CH2:3][C@H:2]([CH3:1])[N:10]([C:11](=[O:23])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)[CH2:9][C:6]3([CH2:7][CH2:8]3)[CH2:5]1)[N:41]=[CH:40]2
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CC2(CC2)CN1C(=O)c1ccccc1-n1nccn1
Reactant: Fc1ccc2nc(Cl)ncc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2ncc3cc(F)ccc3n2)CC2(CC2)CN1C(=O)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.03 g (2.5 mmol) 2-5 in 50 mL CH2Cl2 and 5 mL TFA was allowed to stir at room temperature overnight. The solvents were removed by rotary evaporation, the residue was basified with saturated aqueous Na2CO3, and extracted with three portions of 2:1 CHCl3/EtOH. The organic extracts were concentrated, redissolved in CH2Cl2, filtered and concentrated to provide 765 mg of a taffy. A solution of 116 mg (0.37 mmol) of this material in 3 mL DMF was treated with 68 mg (0.37 mmol) of 1-8 and 130 mL (0.93 mmol) triethylamine and stirred at 60° C. overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3, then with water, brine and dried over Na2SO4. Following concentration by rotary evaporation, the residue was purified by flash column chromatography (EtOAc/hexanes) to provide 2-6 as a pale yellow solid. Data for 2-6: HRMS (APCI) m/z (M+H) 458.2103 found; 458.2099 required.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1S(O)(=O)=O)([O-])=O.[N+:14]([C:17]1[CH:18]=[C:19](S([O-])(=O)=O)[CH:20]=[CH:21][CH:22]=1)([O-])=O.[Na+].[N+](C1C=CC=CC=1)([O-])=O.[OH-].[Na+].N(C1C=CC=CC=1)NC1C=CC=CC=1.S(=O)(=O)(O)O>[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:20]2[CH:19]=[CH:18][C:17]([NH2:14])=[CH:22][CH:21]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1ccc(-c2ccc(N)cc2)cc1

Procedure:
A 2-nitrobenzenesulfonic acid derivative (e.g. sodium 2-nitrobenzenesulfonate) or a 3-nitrobenzenesuflonic acid derivative (e.g. sodium 3-nitrobenzenesulfonate) and nitrobenzene are treated with zinc dust in the presence of an alkali (e.g. sodium hydroxide) and the resulting hydrazobenzene derivative is treated with sulfuric acid, to give the corresponding 4,4′-diaminobiphenyl derivative. This is diazotized using sodium nitrite under acidic conditions in the presence of hydrochloric acid, followed by reaction with sodium azide, to give the desired product.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][CH2:20][CH2:21]O)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C1(C)C=CC(S([Cl:38])(=O)=O)=CC=1>C(#N)C>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][CH2:20][CH2:21][Cl:38])[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2cccc(CCCO)c12
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)c1c[nH]c2cccc(CCCCl)c12
Reaction time: 264 h
Yield: 48 %

Procedure:
To a solution of 3-[3-(phenylsulfonyl)-1H-indol-4-yl]propan-1-ol (1.006 g, 3.19 mmol) in anhydrous acetonitrile (25 mL) at room temperature under nitrogen was added pyridine (0.65 mL, 7.97 mmol) followed by p-toluenesulfonyl chloride, and the reaction mixture stirred for 11 days. The reaction mixture was then concentrated to a small volume in vacuo, and the mixture partitioned between ethyl acetate (100 mL) and 1 N aqueous HCl (100 mL). The organic phase was separated, washed with water (2×100 mL) and brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow syrup. Purification by flash chromatography (0 to 40% ethyl acetate/hexane) afforded 3-phenylsulfonyl-4-(3-chloro-propyl)-1H-indole as a colorless foam (0.51 g, 48%). MS (ES+) m/z 334 (M+H). Further elution afforded 3-[3-(phenylsulfonyl)-1H-indol-4-yl]propyl 4-methylbenzenesulfonate as a white foam (0.48 g, 32%). MS (ES+) m/z 469.7 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(OC2NC(N)=C3C(N=2)=NC(OC)=N3)CCC1.[CH:25]1([O:31][C:32]2[N:40]=[C:39]3[C:35]([N:36]=[C:37]([O:47][CH3:48])[N:38]3C3CCCCO3)=[C:34]([NH2:49])[N:33]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:25]1([O:31][C:32]2[NH:33][C:34]([NH2:49])=[C:35]3[C:39]([N:40]=2)=[N:38][C:37]([O:47][CH3:48])=[N:36]3)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COc1nc2c(N)nc(OC3CCCCC3)nc2n1C1CCCCO1
Agent: COc1nc2nc(OC3CCC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2nc(OC3CCCCC3)[nH]c(N)c-2n1

Procedure:
Prepared similarly to Intermediate 58 from 2-(cyclohexyloxy)-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CS(Cl)(=O)=O>>[C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: COc1ccc(C2(O)CCCCC2)cn1
Agent: CS(=O)(=O)Cl
Product: COc1ccc(C2=CCCCC2)cn1
Yield: 62.8 %

Procedure:
According to Scheme 26 Step 2: The title compound was prepared from 1-(6-methoxypyridin-3-yl)cyclohexanol (1 eq, 1.21 mmol, 0.25 g) and methanesulfonyl chloride (4 eq, 4.82 mmol, 0.37 mL) according to the procedure described for Example 4 Step 1. The crude residue was purified by chromatography over silicagel (AIT Flashsmart prepacked column 10 g SiO2, AcOEt/pentane 30/10 to pure AcOEt), yielding the title compound (0.76 mmol, 0.14 g, 63%) as a colorless oil.