Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C2C(=CC=C(S([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(=O)=O)C=2)C(Cl)=CN=1.N1CCCC[C@@H]1C(O)=O.CC(=C)C.[OH-].[Na+]>O1CCOCC1.O.CCOCC>[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCCN1S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: C=C(C)C
Agent: O=C(O)[C@H]1CCCCN1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@H]1CCCCN1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
tert-Butyl (2R)-1-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-2-piperidinecarboxylate ##STR195## Concentrated H2SO4 (2.0 ml) was added to an ice-cold solution of 2 -(R)-piperidine carboxylic acid (415 mg, 3.21 mmol) in dioxan (10 ml). Condensed isobutylene (40 ml) was carefully added, and the reaction stirred at room temperature in a sealed vessel for 21 h. The reaction mixture was poured into an ice-cooled solution of Et2O (100 ml) and SN NaOH (20 ml), the mixture allowed to warm to room temperature with stirring, and then diluted with water. The phases were separated, the organic layer washed with 1N NaOH, then concentrated in vacuo, to half the volume, and extracted with 2N HCl. The combined acidic extracts were basified using 1N NaOH, and extracted with CH2Cl2, the combined organic solutions dried (MgSO4) and evaporated in vacuo to afford tert-butyl 2(R)-piperidine carboxylate (210 mg, 1.4 mmol) as an oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[CH:11]([O:14][C:15]1[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][C@@H:18]([CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:32][CH2:31]1)[O:19][C@H:20]2[CH2:26][NH:27][CH:28]=O)([CH3:13])[CH3:12]>C1COCC1>[CH:11]([O:14][C:15]1[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][C@@H:18]([CH:30]1[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:34][CH2:35]1)[O:19][C@H:20]2[CH2:26][NH:27][CH3:28])([CH3:13])[CH3:12]
Reactant: Cc1ccc2c(c1OC(C)C)C[C@@H](C1CCN(CCc3ccccc3)CC1)O[C@H]2CNC=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CNC[C@@H]1O[C@H](C2CCN(CCc3ccccc3)CC2)Cc2c1ccc(C)c2OC(C)C
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 0.5M LiAlH4 in THF (3 mL) at 8° C., add of AlCl3 (35 mg) and (1R,3S)-N-[5-Isopropoxy-6-methyl-3-(1-phenethyl-piperidin-4-yl)-isochroman-1-ylmethyl]-formamide in THF (2 mL). Allow the reaction mixture to warm to 20° C. and stir for 4 hours. Cool to 8° C. and quench by slow addition of saturated, aqueous. NH4Cl to pH 8. Add EtOAc (8 mL) and then filter the mixture separate the organic layer and concentrate. Purify the residue by chromatography on a 1 g silica gel column (eluent: 10% CH3OH/CH2Cl2). Collect the appropriate fractions and concentrate to obtain the title compound.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=O)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[C:43](=[O:50])[N:44]([CH3:49])[CH:45]=[C:46]([Br:48])[CH:47]=1>C(Cl)Cl>[Br:48][C:46]1[CH:47]=[C:42]([NH:41][C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[O:7])[C:43](=[O:50])[N:44]([CH3:49])[CH:45]=1
Reactant: O=C(O)C1CCC1
Reactant: Cn1cc(Br)cc(N)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Br)cc(NC(=O)C2CCC2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.8 %

Procedure:
To a mixture or cyclobutanecarboxylic acid (200 mg, 2.0 mmol), HATU (1.14 g, 3.0 mmol) and DIPEA (516 mg, 4.0 mmol) in DCM (8 mL) was added 3-amino-5-bromo-1-methylpyridin-2(1H)-one (330 mg, 1.62 mmol). The reaction mixture was stirred at 25° C. for 5 hours. The resulting mixture was evaporated under reduced pressure and the residue was purified on a silica-gel column eluting with 20:1 DCM/methanol to afford 101a (230 mg, 54%). MS-ESI: [M+H]+ 285.1
Reaction SMILES: C([N:4]([CH2:8][CH3:9])[CH:5]([CH3:7])[CH3:6])(C)C.[C:10]1(C)[CH:15]=CC=C[CH:11]=1.O>CO>[NH:4]1[C:5]2[C:6](=[CH:11][CH:10]=[CH:15][CH:7]=2)[CH:9]=[CH:8]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccccc1
Solvent: O
Solvent: CO
Product: c1ccc2[nH]ccc2c1

Procedure:
In Scheme VIII, Step 4, 4-Benzyloxypropiophenone is brominated in acetic acid with bromine. When the reaction is complete the mixture can be quenched with water and the resulting precipitate is washed with dilute acetic acid, water and heptane. The resulting solid is dried to give IV, 4-benzyloxyaniline hydrochloride. In Step 5, a mixture of IV, N,N-diisopropylethylamine and toluene is heated under reflux with removal of water. When the reaction is complete the mixture may be cooled and diluted with methanol. The solids produced can be collected, washed with methanol and dried to give compound indole V. A mixture of compounds V and III can be mixed in Step 6 with sodium tert-butoxide in N,N-dimethylformamide and stirred until the reaction is complete. Then the mixture may be quenched with brine and extracted with toluene. The extracts are concentrated and the residue diluted with methanol. The resulting solids may be collected, dissolved in ethyl acetate, clarified, and diluted with methanol. The solids may be collected from this dilution and dried to give compound VI.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15](COCC[Si](C)(C)C)[C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:4]1)[CH3:2].Br.[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[NH:15][C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCC[C@@H](Oc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN1CCC[C@@H](Oc2ccnc3[nH]c4cnc(C#N)cc4c23)C1
Temperature: 75 °C
Yield: 37.3 %

Procedure:
(R)-4-(1-ethylpiperidin-3-oxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (46 mg, 0.10 mmol) was dissolved in 1,4-dioxane (0.5 mL) and then treated with 48% HBr(aq) (0.5 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (12 mg, 37%). 1H NMR (400 MHz, d6-DMSO) δ 12.78 (s, 1H), 8.96 (d, J=0.9, 1H), 8.54-8.51 (d, J=5.9, 1H), 8.50 (d, J=0.9, 1H), 7.11 (d, J=5.9, 1H), 4.93-4.83 (m, 1H), 2.98 (d, J=8.9, 1 H), 2.61 (m, 1H), 2.52 (m, 2H), 2.44 (q, J=7.2, 2H), 2.26 (t, J=8.8, 1H), 2.07 (m, 1H), 1.86-1.75 (m, 1H), 1.66 (m, 2H), 1.04 (t, J=7.1, 3H). LCMS (Method E): RT=7.33 min, M+H+=322.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:45]4[CH2:46][CH2:47][CH:42]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH2:43][CH2:44]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(Cl)nn45)ccnc32)cc1
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCC(N7CCCC7)CC6)nn45)ccnc32)cc1
Temperature: 140 °C
Yield: 78.1 %

Procedure:
A mixture of 0.15 g (0.29 mmol) of 6-chloro-2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared according to the method described in step 3.2 of Example 3, and 0.179 g (1.16 mmol) of 4-pyrrolidin-1-ylpiperidine is heated under reflux for 40 hours at 140° C. The reaction medium is cooled. The crystalline solid which forms on cooling is triturated in 1 ml of diisopropyl ether and is isolated by centrifugation and removal of the supernatant in order to give 0.144 g of 2-(4-fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, used without additional purification in the remainder of the synthesis.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:21][CH2:22][CH2:23][CH2:24][CH:25]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:26]([NH:28][NH2:29])=[O:27].[CH3:37][O:38][C:39]1[CH:40]=[C:41](/[CH:51]=[CH:52]/[C:53](O)=[O:54])[CH:42]=[CH:43][C:44]=1[N:45]1[CH:49]=[C:48]([CH3:50])[N:47]=[CH:46]1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH3:37][O:38][C:39]1[CH:40]=[C:41](/[CH:51]=[CH:52]/[C:53]([NH:29][NH:28][C:26](=[O:27])[CH:25]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:24][CH2:23][CH2:22][Cl:21])=[O:54])[CH:42]=[CH:43][C:44]=1[N:45]1[CH:49]=[C:48]([CH3:50])[N:47]=[CH:46]1
Reactant: NNC(=O)C(CCCCl)c1ccc(F)cc1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.4 %

Procedure:
IPEA (1.28 mL), HOBT (330 mg) and EDC (468 mg) were added to a solution of 5-chloro-2-(4-fluorophenyl)pentanoic acid hydrazide hydrochloride (342 mg) and (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (315 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 14 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 427 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])=[CH:7][C:6]=1[O:16][CH3:17].[CH2:18](Br)[C:19]#[CH:20]>CO>[CH3:17][O:16][C:6]1[CH:7]=[C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])[CH:9]=[CH:10][C:5]=1[O:4][CH2:20][C:19]#[CH:18]
Reactant: COc1cc(CCNC=O)ccc1O
Reactant: C#CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#CCOc1ccc(CCNC=O)cc1OC

Procedure:
Sodium methoxide (32 ml of a 5.4 M solution in methanol, 0.17 mol) is added to a solution of N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-formamide (32 g, 0.16 mol) in methanol (400 ml). Propargyl bromide (20 g, 0.17 mol) is added and the mixture is refluxed for 4 hours. After evaporation the residue is taken up in ethyl acetate (400 ml) and washed with water (2×200 ml). The organic layer is dried over magnesium sulfate and evaporated. The residue is submitted to flash-chromatography to give the N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-formamide. 1H-NMR (300 MHz, CDCl3, δ(ppm)): 2.44 (t, 1H, C≡CH), 2.73 (t, 2H, CH2CH2), 3.51 (t, 2H, CH2CH2), 3.82 (s, 3H, OCH3), 4.69 (m, 2H, OCH2), 5.53(bs, 1H, NH), 6.62–6.95 (m, 3H, CH arom.), 8.09 (s, 1H, CHO).
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([F:14])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([F:14])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(C2CCC2)cc1F
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(C2CCC2)cc1F
Yield: 72.2 %

Procedure:
A solution of 4-cyclobutyl-2-fluoro-nitrobenzene (0.5 g, 2.6 mmol) in IMS (5 mL) was degassed with argon for 2 minutes, before 10% Pd/C (0.05 g) was added, and a balloon of hydrogen affixed. The resultant mixture was stirred for 18 hours at room temperature, before being flushed with nitrogen and filtered through hyflo®. The filtrate was concentrated in vacuo to afford the title compound as an orange/red oil (0.31 g, 74%). 1H NMR (CDCl3): 6.84 (1H, d, J=12.3 Hz), 6.77 (1H, d, J=8.1 Hz), 6.70 (1H, t, J=9.1 Hz), 3.58 (2H, broad), 3.42 (1H, m), 2.28 (2H, m), 2.01 (3H, m), 1.82 (1H, m).
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[OH:29][C@@H:26]1[CH2:27][CH2:28][N:24]([C:3]2[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:23][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:25]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)nicotinamide (Stage 208.1) and pyrimidin-5-ylboronic acid to afford a foam. HPLC (Condition 4) tR=5.11 min, UPLC-MS (Condition 3) tR=1.00 min, m/z=480.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.85 (m, J=9.00 Hz, 1H) 2.88 (d, J=11.73 Hz, 1H) 3.14-3.27 (m, 2H) 3.38 (m, J=7.00 Hz, 1H) 4.20 (m, J=2.30 Hz, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.66 (d, J=8.60 Hz, 2H) 7.99 (d, J=8.60 Hz, 2H) 8.10 (d, J=2.35 Hz, 1H) 8.80 (d, J=1.96 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.31 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][CH:6]=1)(=[NH:4])=[O:3].[H-].[K+].Br[CH2:26][C:27]#[N:28].O>COCCOC.[Br-].C([N+](CC)(CC)CC)C>[C:27]([CH2:26][N:4]=[S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:21][CH:22]=1)([CH3:1])=[O:3])#[N:28]
Reactant: CS(=N)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: N#CCBr
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [H-]
Solvent: COCCOC
Solvent: O
Product: CS(=O)(=NCC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(4-(S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione (preparation 17b, 500 mg, 1.59 mmol) and 1,2-dimethoxyethane (2 mL) is added to a mixture of potassium hydride (30%, 260 mg, 1.95 mmol) in 1,2-dimethoxyethane (3 mL). The mixture is stirred for 15 min at room temperature and treated with tetraethylammonium bromide (10 mg, 0.05 mmol) and bromoacetonitrile (220 μL, 3.16 mmol). The mixture is heated at 110° C. over night and cooled to room temperature. Water is added, and the mixture is extracted twice with dichloromethane. The organic layer is concentrated under reduced pressure, and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 1:0 to 0:1). Yield: 155 mg (27% of theory). ESI mass spectrum: [M+H]+=354; r.t. HPLC: 0.47 min (X011_S03).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.I[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]2[CH:14]=[CH:13][CH:18]=[CH:17][C:16]=2[CH2:19][CH2:20][OH:21])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: OCCc1ccc(I)cc1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Product: Cc1ccc(Nc2ccccc2CCO)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 Example 45 from 4-methyl-2-nitroaniline and 4-iodophenylethyl alcohol.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[CH:4][CH:3]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH:40]([O:42]CCCC)=[CH2:41].C1(N(C)C2CCCCC2)CCCCC1.Cl>O1CCOCC1.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].O>[C:40]([C:2]1[N:10]2[C:5]([C:6]3([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[CH:4][CH:3]=1)(=[O:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1c(Br)ccc12
Reactant: C=COCCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc2n1-c1ccccc1OC21CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of tert-butyl 1′-bromospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (1.10 g, 2.60 mmol) and Pd2(dba)3.OCHCl3 (543 mg, 0.525 mmol) in 1,4-dioxane (4.4 mL) was added tri-tert-butylphosphane (360 μL, 1.31 mmol), 1-vinyloxybutane (3.55 mL, 26.2 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (843 μL, 3.94 mmol). The mixture was heated at 80° C. for 5 hours. The mixture was cooled to room temperature before 1N HCl (3 mL) was added and the mixture was stirred for 1 hour. The mixture was poured into water and was extracted with ethyl acetate (4×). The organics were combined, washed with water (2×), brine and evaporated. The residue was purified by column chromatography (0-20% ethyl acetate in hexanes) to give tert-butyl 1′-acetylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (610 mg, 61%) as a yellow solid. ESI-MS m/z calc. 382.2, found 383.1 (M+1)+; Retention time: 1.97 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J=8.1, 1.3 Hz, 1H), 7.35 (d, J=4.1 Hz, 1H), 7.24-7.12 (m, J=9.4, 8.0, 1.6 Hz, 2H), 7.08-6.98 (m, 1H), 6.35 (d, J=4.1 Hz, 1H), 3.88 (d br, J=11.3 Hz, 2H), 3.13 (s br, 2H), 2.49 (s, 3H), 1.92-1.76 (m, 4H), 1.41 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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]>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[CH3:9])=[CH:13][CH:12]=1
Reactant: Cc1cc(N)ccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(N)ccc1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
4-bromo-3-methylaniline (5.1 g, 27.4 mmol), 4-chlorophenylboronic acid (5.1 g, 32.9 mmol), Pd(dppf)Cl2 (1.1 g, 1.4 mmol), and 2M aqueous K2CO3 (27.4 mL, 54.8 mmol) were dissolved in 1,4-dioxane (110 mL) and the resulting mixture was heated to 100° C. After 2 h the resulting mixture was cooled to room temperature, concentrated, diluted with EtOAc and 4M aqueous NaCl, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O1CCCC1.C(OCC)C>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccc(Oc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A solution of 4-phenoxyphenylmagnesium bromide in tetrahydrofuran (30 mL, 15 mmol) is introduced in a flame dried flask placed under argon atmosphere. A solution of 1-benzyl-4-piperidone (2.84 g, 15 mmol) in dry tetrahydrofuran (12 mL) is added dropwise, while the temperature is maintained below 20° C. with an ice bath. After completion of the addition, the mixture is allowed to reach room temperature and is further stirred for 2 hours. Ice is then added to the reaction mixture and 1 N hydrochloric acid is added until the precipitate formed is completely dissolved. The reaction is then diluted with diethyl ether (100 mL) and washed with water (50 mL). The aqueous layer is then extracted with diethyl ether (2×50 mL) and the combined organic layers are sequentially washed with saturated aqueous sodium hydrogencarbonate (2×50 mL) and with water (50 mL), are then dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product is then purified by column chromatography on silica gel (dichloromethane and then diethyl ether). The desired product is isolated as a colorless solid (1.74 g, 33% yield).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[CH3:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]=[O:13])[CH2:8][CH2:7]1.[Cl-].[NH4+].Cl>O1CCCC1>[CH3:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]([OH:13])[CH2:1][CH3:2])[CH2:8][CH2:7]1
Reactant: CC1CCC(C=O)CC1
Reactant: CC[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)C1CCC(C)CC1
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
180 ml (0.36 mol) of a 2 M ethylmagnesium chloride solution in tetrahydrofuran (THF) was first treated with a solution of 37.8 g (0.3 mol) of 4-methylcyclohexanecarbaldehyde (cis/trans) in 70 ml of THF and then stirred under protective gas atmosphere for approximately 16 hours at 20-25° C. After addition of 250 ml of 15% by weight ammonium chloride solution, the mixture was acidified with semiconcentrated hydrochloric acid and then extracted with methyl tert-butyl ether (MTBE). Washing of the combined organic phases with water and drying gave 44 g of 1-(4-methylcyclohexyl)propan-1-ol as a colorless oil. According to 1H NMR analysis, the ratio between the cis and trans isomers in the mixture amounted to approximately 35:65.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[C:13]3[NH:20][CH:19]=[C:18]([C:21]([OH:23])=O)[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:3][CH2:2]1.[C:24]([O:28][C:29](=[O:38])[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:38])[NH:30][C@H:31]1[CH2:32][CH2:33][C@H:34]([NH:37][C:21]([C:18]2[C:14]3[N:15]=[CH:16][N:17]=[C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:13]=3[NH:20][CH:19]=2)=[O:23])[CH2:35][CH2:36]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(O)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A78) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][S:7]([CH:10]([CH3:12])[CH3:11])(=[O:9])=[O:8].[CH3:16][S:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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].ClCCl>[CH3:16][S:17]([C:20]1[CH:25]=[C:24]([C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([CH2:5][NH:6][S:7]([CH:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH:3]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)S(=O)(=O)NCc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NCc1cccc(-c2cccc(S(C)(=O)=O)c2)c1

Procedure:
In analogy to example 1, step 3, propane-2-sulfonic acid 3-bromo-benzylamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give propane-2-sulfonic acid (3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide as an off-white solid.