Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[C:14]2[CH2:13][CH2:12][C:11]3[O:15][CH:16]=[CH:17][C:10]=3[C:9]=2[N:8]=[C:7]([NH2:18])[N:6]=1)(=O)=O.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>COCCO>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:5]2[C:14]3[CH2:13][CH2:12][C:11]4[O:15][CH:16]=[CH:17][C:10]=4[C:9]=3[N:8]=[C:7]([NH2:18])[N:6]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)c1nc(N)nc2c1CCc1occc1-2
Solvent: COCCO
Product: CN1CCN(c2nc(N)nc3c2CCc2occc2-3)CC1
Temperature: 110 °C

Procedure:
The product from Example 19A (26 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), treated with 70% 3-chloroperoxybenzoic acid (83 mg, 0.34 mmol), stirred at room temperature for 1 hour, treated with sodium sulfite solution, treated with sodium bicarbonate solution, and extracted with dichloromethane (2×). The combined dichloromethane layers were dried (magnesium sulfate), filtered, concentrated and chromatographed using ethyl acetate in dichloromethane to provide the sulfone intermediate, 4-(methylsulfonyl)-5,6-dihydrofuro[2,3-h]quinazolin-2-amine. This sulfone intermediate was treated with excess 1-methylpiperazine (110 mg, 1.1 mmol) in 2-methoxyethanol (1 mL) heated to 110° C. over night. The reaction mixture was cooled and partitioned between 1 M sodium hydroxide and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane (2×). The combined dichloromethane layers were dried (magnesium sulfate), filtered, concentrated and chromatographed (2, 3.5 and 5% (9:1 methanol:concentrated ammonium hydroxide) in dichloromethane) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ 2.36 (s, 3H), 2.55 (t, J=4.7 Hz, 4H), 2.81 (m, 2H), 2.93 (m, 2H), 3.33 (t, J=4.7 Hz, 4H), 4.80 (br s, 2H), 7.13 (d, J=5.1 Hz, 1H), 7.53 (d, J=5.1 Hz, 1H); MS (DCI/NH3) m/z 286 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:22])[C:17]([C:23]([OH:25])=O)=[CH:16]2.[NH2:26][C@H:27]([C:31]([NH:33][CH:34]([CH:43]([OH:46])[CH2:44][F:45])[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[CH:28]([CH3:30])[CH3:29]>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:22])[C:17]([C:23]([NH:26][C@H:27]([C:31]([NH:33][CH:34]([CH:43]([OH:46])[CH2:44][F:45])[CH2:35][C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:25])=[CH:16]2
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1cc2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
DMAP (257 mg, 2.08 mmol) and EDAC (427 mg, 2.23 mmol) were added as solids to a solution of 5-fluoro-1-methylindole-2-carboxylic acid (359 mg, 86 mmol in 3 mL of DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. N-(Valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (579 mg, 1.86 mmol) in DMF (3 mL) was added and the resulting solution was stirred for 1 hour under a nitrogen atmosphere at 0° C. and 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give the title product as a slightly yellow solid (0.827 mg). TLC(methanol/methylene chloride, 1:9): Rf =0.52.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(O)(=O)C.[N+:15]([O-])([OH:17])=[O:16]>>[F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(F)c1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=Cc1cc([N+](=O)[O-])cc(F)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a flask with 3-fluoro-2-hydroxybenzaldehyde (5.00 g, 35.7 mmol) in acetic acid (10 mL, 175 mmol), was added nitric acid (conc., 10 mL, 244 mmol) at 0° C. The mixture was stirred 0° C. for 30 min, quenched with ice, extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated to give 17C (5.457 g, 29.5 mmol, 83% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:21]([CH3:23])[CH3:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=2)[C:15]([NH2:17])=[S:16])=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[CH3:29][C:30](O)=O>C(OC(OCC)CBr)C.CC1C=CC(S(O)(=O)=O)=CC=1>[CH:21]([C:11]1[CH:12]=[C:13]([O:19][CH3:20])[C:14]([C:15]2[S:16][CH:29]=[CH:30][N:17]=2)=[CH:18][C:10]=1[O:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1)([CH3:23])[CH3:22]
Reactant: CC(=O)O
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(N)=S
Agent: CCOC(CBr)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-c1nccs1
Temperature: 110 °C
Yield: 28 %

Procedure:
To a solution of 5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-thiobenzamide (0.23 g, 0.69 mmol) in HOAc (5 ml) was added bromoactaldehyde diethylacetal (0.18 g, 0.9 mmol) and TsOH (5 mg) as a catalyst. The reaction mixture was heated at 110° C. for 16 hrs and basified with sat. NaHCO3 solution. The aqueous solution was extracted into methylene chloride. The combined organic extract was dried over Na2SO4, filtered and concentrated. Flash chromatography on silica (5% MeOH in methylene chloride with 1% NH4OH) gave 5-(2-Isopropyl-4-methoxy-5-thiazol-2-yl-phenoxy)-pyrimidine-2,4-diamine (0.070 g, 28% ) as a yellow solid. (M+H)=358
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].S(Cl)([Cl:29])=O>>[CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([Cl:29])=[O:23])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Undecylpyrimidine-2-yl)benzoic acid (1.70 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-undecylpyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[CH3:28])[CH:20]=4)=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1ccccc1Cn1cc(C(O)c2c(C)noc2-c2ccc(Br)cc2)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccccc5C)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-methyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1Br)(=[O:15])=[O:14]>CN(C)C=O>[CH3:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:11][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1sccc1Br
Reactant: SCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1sccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 g of sodium methoxide in 100 ml of dimethylformamide was added 6 ml of benzyl mercaptan followed by 10 g of 3-bromo-2-thienyl methyl sulfone. The temperature rose to 70°. The mixture was stirred at room temperature for 16 hours and then at 70° for 1 hour. Most of the dimethylformamide was evaporated at reduced pressure and ice-water was added to the residue. The resulting solid was filtered, washed with ice-water and hexane to afford 14 g of crude XXVII. A dried sample of this material had m.p. 95°-97° and peak at 4.2 in the NMR spectrum (CDCl3), consistent with an aromatic benzyl sulfide.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:24])[C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([O:22]C)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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].C(Cl)Cl.CS(C)=O>[F:24][C:4]1[C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([OH:22])=[CH:15]4)=[N:9][N:10]=2)[CH:7]=[C:2]([C:29]2[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=2)[CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cnc2ccc(Cc3nnc4c(F)cc(Cl)cn34)cc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: COCCOC
Solvent: ClCCl
Product: Cn1cc(-c2cc(F)c3nnc(Cc4ccc5ncc(O)cc5c4)n3c2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
A mixture of crude 6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline (200 mg, 584 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (600 mg, 2884 μmol), PdCl2(dppf)-CH2Cl2 adduct (24 mg, 29 μmol), and Na2CO3 (500 mg, 4717 μmol) in DME (7 mL)-H2O (5 mL) was heated at 100° C. under nitrogen. After overnight, the sludge was treated with DMSO (10 mL) and filtered. The DMSO solution was purified on HPLC (10-60%/10 min). The product fraction was concentrated to dryness with toluene. The solid was then triturated with MeOH-hexane (1:2) to give a brown powder (60 mg). LCMS (ESI pos. ion): calc'd for C20H15FN6O: 374.1. found 375.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23].Br.Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[N:21]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[N:20]=[N:19][N:18]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23]
Reactant: CCCc1c(OCCCCCc2nnn[nH]2)ccc(C(C)=O)c1O
Reactant: BrCCCCc1cccnc1
Agent: Br
Product: CCCc1c(OCCCCCc2nnnn2CCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
1-[2-Hydroxy-3-propyl-4-[5-(1H-tetrazol-5-yl)pentyloxy]phenyl]ethanone was allowed to react with 3-(4-bromobutyl)pyridine hydrobromide according to procedure B and the product was purified by high pressure liquid chromatography to give 1-[2-hydroxy-3-propyl-4-[5-[1-[4-(3-pyridinyl)butyl]-1H-tetrazol-5-yl]pentyloxy]phenyl]ethanone, which is the N-1 isomer, and 1-[2-hydroxy-3-propyl-4-[5-[2-[4-(3-pyridinyl)butyl]-2H-tetrazol-5-yl]pentyloxy]phenyl]ethanone, which is the N-2 isomer.
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C:4]([NH:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[OH:16])=[O:5])[CH3:2]>C(O)C.[H][H].[Ni]>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]([OH:16])=[C:7]([NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=1
Reactant: [H][H]
Reactant: CCCCC(CC)C(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: [Ni]
Solvent: CCO
Product: CCCCC(CC)C(=O)Nc1cc(N)ccc1O
Reaction time: 2 h

Procedure:
39 g of preliminary product 1 were hydrogenated with H2 /Raney nickel in 200 ml ethanol. The hydrogenation was conducted over a period of 2 hours and within a temperature range from 20 to 40 C. at a pressure of 2. 106Pa. The catalyst was filtered off under suction and 400 ml water were added. The dried, oily product (37 g) which was separated was reacted further without additional purification.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:26])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+]>CO.C(#N)C.O1CCCC1>[NH2:33][CH:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:26])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(CC(=O)N(C)C)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(CC(=O)N(C)C)CC1
Temperature: 65 °C

Procedure:
A mixture of 2-[4-(7-acetyl-5-chloroquinolin-8-yl)piperazin-1-yl]-N,N-dimethylacetamide (0.019 g, 0.051 mmol) and ammonium acetate (0.0391 g, 0.507 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.12 mL). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H27ClN5O (M+H)+: m/z=376.2; Found: 376.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])(C)C)=[O:14])[CH2:9][CH2:8]1.Cl.C(OC(Cl)=O)[C:22]1[CH:27]=[CH:26]C=[CH:24][CH:23]=1>O1CCOCC1>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:19]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[O:14])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCC(C2CC2CCO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cis tert-butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (2.0 g, 7.44 mmol) was treated with 4M HCl in dioxane (200 mL) at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue taken up in 200 mL DCM. To this solution was added TEA (10.0 mL, 7.64 mmol) followed by benzylchloroformate (1.30 g, 7.64 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was washed with 1N aqueous HCl (75 mL), followed by saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via Biotage (40M+ silica gel) eluting with a gradient of 0-80% ethyl acetate to afford the title compound as a viscous oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](Cl)=[O:37])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:18]([CH:16]2[CH:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[O:37])=[CH:31][CH:30]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Cc1ccc(Cl)cc1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 88, the title compound 2-(4-chloro-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-chlorophenylacetyl chloride instead of 4-fluorobenzoyl chloride and was obtained as an off-white semi-solid. MS m/e: 562.2 [M]+.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:14]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:13]([NH:23][CH:24]([CH3:26])[CH3:25])[N:12]=[C:11](Cl)[N:10]=1)[CH2:2]2.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)=[O:36])[CH:29]=1>>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:14]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:13]([NH:23][CH:24]([CH3:26])[CH3:25])[N:12]=[C:11]([C:41]3[CH:40]=[CH:39][C:38]([NH:37][C:35]([NH:34][C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)=[O:36])=[CH:43][CH:42]=3)[N:10]=1)[CH2:2]2
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccnc3)cc2)OC1(C)C
Reactant: CC(C)Nc1nc(Cl)nc(N2CC3CCC(C2)O3)c1NC(=O)CCN(C)C
Product: CC(C)Nc1nc(-c2ccc(NC(=O)Nc3cccnc3)cc2)nc(N2CC3CCC(C2)O3)c1NC(=O)CCN(C)C

Procedure:
N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(isopropylamino)-2-(4-(3-pyridin-3-ylureido)phenyl)pyrimidin-5-yl)-3-(dimethylamino)propanamide was prepared by Suzuki coupling using the general method from scheme 2 for the preparation of 6 using N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-6-(isopropylamino)pyrimidin-5-yl)-3-(dimethylamino)propanamide (49, 0.050 g, 0.126 mmoles) and 1-(pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (52, 0.047 g, 0.139 mmoles). The crude product was purified by HPLC to provide the title compound as a yellow solid. Yield: 0.049 g (68%). HRMS; [M+H]+ Calc'd=574.3249, [M+H]+ Obs'd=574.3241.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:28])=[C:5]([C@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]3[CH2:12]2)[CH:6]=[C:7]([CH3:10])[C:8]=1[F:9])#[N:2].FC1C(C#N)=C(C)C([C@H]2OC[C@H]3CNCCN3C2)=CC=1>>[C:1]([C:3]1[C:4]([CH3:28])=[C:5]([C@H:11]2[O:16][CH2:15][C@H:14]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20][N:13]3[CH2:12]2)[CH:6]=[C:7]([CH3:10])[C:8]=1[F:9])#[N:2]
Reactant: Cc1cc([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)c(C)c(C#N)c1F
Agent: Cc1c([C@@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N
Product: Cc1cc([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)c(C)c(C#N)c1F

Procedure:
(3R,9aR)-tert-Butyl 3-(3-cyano-4-fluoro-2,5-dimethylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate was prepared in an analogous fashion to that described for the synthesis of (3R,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2,5-dimethylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate starting from 6-fluoro-2-methyl-3-((3R,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][C:5]([C:13]2[C:17]([CH3:18])=[C:16]([C:19]#[N:20])[N:15]([CH3:21])[N:14]=2)=[C:4]([F:22])[CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:13]2[C:17]([CH3:18])=[C:16]([C:19]#[N:20])[N:15]([CH3:21])[N:14]=2)=[C:4]([F:22])[CH:3]=1
Reactant: CCOC(=O)c1cc(-c2nn(C)c(C#N)c2C)c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(-c2cc(C(=O)O)c(Cl)cc2F)nn(C)c1C#N

Procedure:
3.1 g of 3-(4-chloro-2-fluoro-5-carbethoxyphenyl)-4-methyl-5-cyano-1-methyl-[1H]-pyrazole (Example H13) are dissolved in 22 ml of dioxane, and 10 ml of 2N aqueous sodium hydroxide solution are added dropwise at 22° C. The mixture is stirred until the reaction is complete, the solvent is evaporated, the resulting residue is dissolved in water and the solution is brought to pH 1using hydrochloric acid. The precipitate formed is filtered off and dried. This gives the desired product in a yield of 2.63 g (89.8% of theory).
Reaction SMILES: N1C(C)=CC(C)=CC=1C.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>ClCCl>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: OCCCCCCCCCCBr
Reactant: C=C(C)C(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
2,4,6-Collidin (12.3 ml, 92.7 mmol, 1.1 eq.) was added to a solution of 10-bromodecanol (20.0 g, 84.3 mmol) in anhydrous dichloromethane (200 ml). After cooling the mixture to 0° C. methacrylic acid chloride (16.5 ml, 168.6 mmol, 2 eq.) was slowly added dropwise and the reaction mixture was stirred for 1 h at 0° C. and at for 15 h room temperature. The reaction mixture was then washed with water (100 ml) and cold 1N HCl (100 ml). The combined organic phases were dried with anhydrous sodium sulphate. After removal of the solvent under reduced pressure the obtained crude product was purified by column chromatography (eluent: hexane/dichloromethane 8:2). 18.0 g (70% yield) of the product was obtained as a colorless liquid.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1ccc([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of 2-methoxy-4-nitro-benzoic acid (20 g, 0.102 mol) in 80 ml of CH2Cl2 at 0° C. was added BBr3 (1.0 M, 150 ml, 1.5 eq.). The resulting mixture was allowed to warm to rt and stirred for 2 h. MeOH was then added dropwise to quench the reaction at 0° C. and the volatile fraction was removed in vacuo. The residue was purified on a silica gel column with 6/4/0.3 of hexane, EtOAc and HOAc to give 18 g of 2-hydroxy-4-nitro-benzoic acid (M+: 183).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10]([S:20](Cl)(=[O:22])=[O:21])=[CH:9][CH:8]=1)(=O)C.[NH3:24].CO>>[OH:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10]([S:20]([NH2:24])(=[O:22])=[O:21])=[CH:9][CH:8]=1
Reactant: N
Reactant: CC(=O)OCCc1ccc(S(=O)(=O)Cl)c2c([N+](=O)[O-])cccc12
Solvent: CO
Product: NS(=O)(=O)c1ccc(CCO)c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Solid 4-(2-acetoxy-ethyl)-8-nitro-naphthalene-1-sulfonyl chloride (39.64 g, 111 mmol) was added to an ice-cold, 6.8 M solution of ammonia in methanol (408 mL, 277 mmol). The cooling bath was removed, the reaction flask was stoppered, and the reaction was stirred at room temperature. After 4 days, the dark amber solution was concentrated under vacuum to a dark gum. The residue was triturated vigorously shaken with water (300 mL) to give a solid which was washed with water (150 mL) then ether (150 mL) and dried under vacuum. The resulting brown solid was recrystallized from isopropanol (300 mL) to afford 4-(2-hydroxy-ethyl)-8-nitro-naphthalene-1-sulfonamide (27.79 g) as tan flakes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH3:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH2:13])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: N
Solvent: c1ccncc1
Product: NS(=O)(=O)c1c(Cl)cccc1Cl
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 2,6-dichlorobenzenesulfonyl chloride (10.50 g, 42.77 mmol) in 100 mL of pyridine was added dropwise to 100 mL of pyridine while anhydrous ammonia gas was bubbled through the solution. After 4 hours at 0° C., the mixture was acidified to pH>1 with 6N aq. HCl, then extracted with ethyl acetate. The combined organic layer was then dried (Na2SO4) and concentrated to give the desired product (8.69 g, 90%). EI-MS (m/z) 225.0, 227.1 (M−).