Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([O:24]CC)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+].C(O)COCCO.Cl>O>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(OCC)cn3)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Yield: 89.1 %

Procedure:
0.5 g (1.42 mM) of 2-octyl-5-(5-ethoxypyrimidine-2-yl)indan, 1.0 g (25 mM) of NaOH and 10 ml of diethylene glycol were mixed and refluxed for 3 hours under stirring. After the reaction, the reaction mixture was poured into water and acidified with HCl to precipitate a crystal. The crystal was recovered by filtration and washed with water. The resultant crystal was dissolved in toluene and washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=1/10) to obtain 0.41 g of 2-octyl-5-(5-hydroxypyrimidine-2-yl)indan (Yield: 89.0%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[S:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Sn](Cl)(Cl)(Cl)Cl.O>C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: c1ccsc1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: O=C(CCCCCBr)c1cccs1
Reaction time: 1 h
Yield: 120.7 %

Procedure:
6-Bromohexanoyl chloride (2.1 g) and thiophene (0.84 g) were dissolved in benzene (20 ml) and tin chloride (1.3 ml) was added under ice-cooling, which was followed by stirring for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 3.1 g of 6-bromo-1-(2-thienyl)-1-hexanone.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23].C([BH3-])#N.[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Reactant: CN(C)CCN
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)CCNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 90.6 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), N,N-dimethylethylenediamine (90 μL, 72 mg, 0.82 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-{3-[(2-dimethylaminoethylamino)methyl]-phenoxy}benzonitrile fumarate (315 mg, 90%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:17]([NH:21][NH2:22])([O:19][CH3:20])=[O:18].CC(O)=O>C(O)C.O>[C:17]([NH:21][N:22]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)([O:19][CH3:20])=[O:18]
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COC(=O)NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)NN=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
To a solution of 4-(4-fluorophenoxy)benzaldehyde (277 mg, 1.28 mmol) in ethanol (10 mL) was added a solution of carbomethoxyhydrazine (180 mg, 2.0 mmol) in water (5 mL), followed by AcOH (0.1 mL) at room temperature. The mixture was stirred at room temperature for 17 h and water (20 mL) was added. The resulting solid was collected by filtration, washed with water and dried in vacuo to yield the title compound as a white solid (228 mg, 0.74 mmol, 58%), mp: 109-111° C. 1H NMR (DMSO-d6): δ 11.05 (s, 1H), 8.00 (s, 1H), 7.64 (d, J=8.7, 2H), 7.30-6.99 (m, 6H), 3.69 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccccc1CCBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-2-chlorobenzene and isolated as light-yellow gum. MS(m/e): 421.3 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].O>CN(C)C=O.C(OCC)(=O)C>[NH:22]1[C:20]([CH2:19][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][CH2:11][C:2]2[N:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[N:21][N:24]=[N:23]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1cccc(OCc2ncc3ccccc3n2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cc(Cc2nnn[nH]2)cc(OCc2ncc3ccccc3n2)c1
Temperature: 135 °C
Yield: 54.6 %

Procedure:
To a solution of 6.3 g (0.023 mol) of 3-(2-quinazolinylmethoxy)benzenacetonitrile in 150 ml of dimethylformamide are added 7.5 g (0.115 mol) of sodium azide and 6.2 g (0.115 mol) of ammonium chloride, and the slurry is heated to 135° C. for 72 hours. The slurry is poured into 500 ml of water/500 ml of ethyl acetate, and the layers are separated. The aqueous phase is twice extracted with 250 ml of ethyl acetate, and the combined ethyl acetate solution is twice washed with 500 ml of water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 4 g of crystals, m.p. 129°-131° C. Recrystallization from ethanol gives 2.5 g (34%) of crystals, m.p. 129°-131° C., MS(CI) 319 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:22])[C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:6]=[CH:7][C:8]=1[S:9][CH3:10].[BH4-].[Na+]>C1COCC1>[OH:22][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([S:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH3:13]
Reactant: COc1cc(C(=O)[C@@H](C)NC(=O)OC(C)(C)C)ccc1SC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(O)[C@@H](C)NC(=O)OC(C)(C)C)ccc1SC
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-t-butyl 1-(3-methoxy-4-(methylthio)phenyl)-1-oxopropan-2-ylcarbamate (308d, 55 μg, 170 μmol) in THF (2 mL) at r.t. was added sodium tetrahydroborate (48 μg, 1.27 mmol) in small portions, and the mixture was stirred for 3 h.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33](Cl)=[N:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:21]([O:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([O:20][C:16]3[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:7]4[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=4)=[O:12])[CH:19]=[CH:18][CH:17]=3)=[N:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OCc5ccccc5)ccc34)c2)no1
Temperature: 50 °C
Yield: 38.5 %

Procedure:
Following to the procedure described in Example 41C, 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (1.02 g, 3.7 mmol) from Example 1A was reacted with 7-(benzyloxy)-4-chloroquinazoline (1 g, 3.7 mmol) and cesium carbonate (24 g, 7.4 mmol) in anhydrous tetrahydrofuran (10 mL) and the mixture was heated at 50° C. overnight. The crude product was triturated with dichloromethane to give 1-(3-(7-(benzyloxy)quinazolin-4-yloxy)phenyl)-3-(5-tert-butylisoxazol-3-yl)urea (725 mg, 38%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.65 (s, 1H), 8.29 (d, 1H), 7.57-7.38 (m, 9H), 7.28 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 5.37 (s, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 510 (M+H)+.
Reaction SMILES: C[Al](C)C.[CH3:5][NH2:6].C(O[C:10]([C:12]1[N:13]=[N:14][C:15]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[CH:16][CH:17]=1)=[O:11])C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCOCC1>[CH3:5][NH:6][C:10]([C:12]1[N:13]=[N:14][C:15]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[CH:16][CH:17]=1)=[O:11]
Reactant: CN
Reactant: CCOC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 800 □L, 1.6 mmol) was added dropwise (exothermic) to a solution of methylamine (2 M in THF, 800 □L, 1.6 mmol) in dioxane (10 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) in dioxane (5 mL) was added. The resulting mixture was heated at 85-95° C. for 18 h, cooled to room temperature, poured into a sodium potassium tartrate solution and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (122 mg, 99%) which was obtained as a white solid. MS: m/e=343.3 [M+H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=2)=[CH:15][C:14](C(N2CCOCC2)=O)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.NCCC1C2C(=CC=C([C:56]3[C:57]([CH3:65])([CH3:64])[C:58](=[O:63])[N:59]([CH2:61][CH3:62])[N:60]=3)C=2)NC=1C1C=C(C)C=C(C)C=1.[NH4+].[OH-]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:29][CH:30]=2)=[CH:15][C:14]([C:56]2[C:57]([CH3:65])([CH3:64])[C:58](=[O:63])[N:59]([CH2:61][CH3:62])[N:60]=2)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Reactant: CCN1N=C(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCN)c3c2)C(C)(C)C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCN1N=C(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCNCCCCc4ccc(NS(C)(=O)=O)cc4)c3c2)C(C)(C)C1=O
Yield: 55 %

Procedure:
Reductive amination of 4-[4-(methanesulfonamido)phenyl] butyraldehyde (EXAMPLE 4) with 5-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-ethyl-4,4-dimethyl-2,4-dihydropyrazol-3-one was carried out according to the method of Example 6.2, Step F, except that 90:10 CH2Cl2-MeOH was used to develop the preparative TLC plates, while 90:10:1 CH2Cl2-MeOH-concd. NH4OH was used to extract the product. This gave a 55% yield of very pale golden-yellow glass; homogeneous by TLC in 92.5:7.5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=628.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7](I)[C:6]=2[C:18]=1[F:19].C([Li])CCC.N1([CH:31]=[O:32])CCCCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([CH:31]=[O:32])[C:6]=2[C:18]=1[F:19]
Reactant: Fc1ccc(-c2oc3ccc(Cl)c(F)c3c2I)cc1
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(-c2ccc(F)cc2)oc2ccc(Cl)c(F)c12
Temperature: 78 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a mixture of 5-chloro-4-fluoro-2-(4-fluorophenyl)-3-iodobenzofuran (2.0 g, 5.12 mmol) in THF (15 ml) under a N2 atmosphere in a 50 ml two necked RB flask cooled to 78° C. was added n-butyllithium (0.328 g, 5.12 mmol) slowly, and the mixture stirred at the same temperature for 1 hour. 1-Piperidinecarboxaldehyde (5.79 g, 51.2 mmol) was then added and the mixture was maintained stirring at the same temperature for 3 hours. The reaction mixture was quenched with 1N HCl and extracted with diethyl ether (3×25 ml). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the titled compound (1.2 g, 74%). 1H NMR (400 MHz, CDCl3): δ 10.39 (d, J=2.4 Hz, 1H), 8.18-8.14 (m, 2H), 7.44-7.40 (m, 1H), 7.33 (d, J=9.2, 1H), 7.27-7.23 (m, 2H).
Reaction SMILES: C(O[C:9]1[CH:14]=C[C:12]([C:15]2[CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.Cl.[NH2:29]N>C(O)C>[N:29]1[CH:14]=[CH:9][CH:10]=[CH:11][C:12]=1[C:15]1[CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:18](=[O:21])[NH:19][N:20]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]c1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccn2)n[nH]c1=O

Procedure:
Working as in example 19 for the preparation of ethyl 6-[4-(benzyloxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate, but starting with 31.1 g of diethyl hydroxy(pyridin-2-oxoethyl)malonate, 11.55 g of hydrazine dihydrochloride and 700 cm3 of ethanol, and after purification by chromatography on silica gel (particle size 40-63 μm, under an argon pressure of 150 kPa), eluting with dichloromethane, followed by recrystallization from ethanol, 6.9 g of ethyl 6-pyridin-2-yl-3-oxo-2,3-dihydropyridazine-4-carboxylate were obtained in the form of a yellow solid melting at 182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[Cl:21].CO>C1COCC1.[Ni]>[Cl:21][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(C=C/C=C/c2ccc(Cl)c(Cl)c2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(CCCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 77.1 %

Procedure:
The title compound was prepared from (trans), (trans)-1,2-dichloro-4-[4-(4-nitrophenyl)-1,3-butadienyl]benzene (15.42 g, 0.048 mol), Ra—Ni (1 g) at 20° C. to 26° C. (ΔP=19.3 psi) under a hydrogen atmosphere in THF (75 mL) and MeOH (75 mL) using the procedure described in Example 1, Step B. This procedure yield a solid, 10.97 g (0.037 mol, 78%) of the desired product. mp 50-52° C.
Reaction SMILES: N[C:2]1[C:7]([C:8]#N)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:11][CH2:12]N(C(C)C)C(C)C>C(O)CCC.O.CCOC(C)=O.CCCCCC>[N:3]1[C:2]2[CH:7]=[CH:8][CH:11]=[CH:12][C:6]=2[NH:5][CH:4]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: c1ccc2[nH]cnc2c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
Synthesis of D-7. A mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (B) (0.257 g, 1.662 mmol), D-6 (1.662 mmol), and DIEA (0.868 mL, 4.99 mmol) in n-butanol (16.62 mL) was stirred at 120° C. After 24 h, the heat was removed and left at rt. After cooling, the mixture was concentrated under reduced pressure to give a brown solid, which was suspended in water (50 mL), sonicated, filtered, and washed with water (100 mL) to give a tan solid. The tan solid was suspended in EtOAc-hexane (1:4, 20 mL), filtered, washed with EtOAc-hexane (1:4, 20 mL), and dried to give D-7 as a racemic mixture.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30]>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([NH:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: COCCCN
Product: COCCCNc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and 3-methoxy-propylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (t, J=5.8 Hz, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.47-7.50 (m, 2H), 7.24 (t, J=5.4 Hz, 1H), 6.82 (d, J=9.2 Hz, 1H), 3.39-3.42 (m, 4H), 3.20-3.22 (m, 5H), 2.01-2.03 (m, 2H), 1.73-1.85 (m, 7H), 1.22-1.31 (m, 2H). m/z: 426.0 [M+H]+
Reaction SMILES: [CH:1]([NH:3][CH2:4][N:5]([CH3:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[ClH:22]>CCOCC.C(O)C.CCOCC.O>[ClH:22].[ClH:22].[CH3:1][NH:3][CH2:4][N:5]([CH3:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CN(CNC=O)CC1CCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CNCN(C)CC1CCCCC1

Procedure:
N-Formylaminomethylcyclohexyldimethylamine prepared as in Example 3 (9.0 g. 0.05 mole) was dissolved in dry ether (100 ml) and added dropwise to a stirred suspension of lithium aluminium hydride (3.8 g. 0.1 mole) in dry ether (200 ml). The suspension was refluxed for 24 hr. and excess lithium aluminium hydride decomposed by dropwise addition of water (8 ml), 30% sodium hydroxide solution (6 ml), and water (28 ml). The ether layer was separated, dried (Na2-SO4), and evaporated to give a colourless mobile oil (7.8 g. 94.2%). An aliquot of this oil was treated with 10% ethanolic hydrochloric acid to give colourless needles of N-methylaminomethylcyclohexyldimethylamine dihydrochloride, m.p. 232°-233°(from ethanol/ether).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12].C(O)C>>[CH2:11]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCN
Solvent: CCO
Product: CCNc1ncccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 92 %

Procedure:
2-Chloro-3-nitropyridine (20.00 g, 126 mmol) was added to ethylamine in ethanol (40 mL, 80 mmol) at room temperature and kept overnight. The solution was evaporated, the residue was diluted with 150 mL of EtOAc, washed with aqueous NaHCO3 and purified by column chromatography on silica gel (hexane/ethyl acetate 4/1) to give yellow solid (19.5 g, 92%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH:17]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[NH:14][C:11]2=[N:12][CH:13]=1)(C)(C)C.[ClH:36]>ClCCl>[ClH:36].[CH3:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:17]([C:15]2[NH:14][C:11]3=[N:12][CH:13]=[C:8]([NH2:7])[CH:9]=[C:10]3[CH:16]=2)[CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:30][CH:29]=1)(=[O:32])=[O:33]
Reactant: CC(C)(C)OC(=O)Nc1cnc2[nH]c(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2cc3cc(N)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of {2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (520 mg, 1.05 mmol) in dichloromethane (10 mL) was treated with dry hydrogen chloride gas for 30 min. The resulting mixture was stirred for 3 h at room temperature. The solvent was removed to afford 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-ylamine hydrochloride salt (454 mg, 100%): LC/MS m/e calcd for C21H25N3O3S [M+H]+ 400.52, observed 400.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[Cl:10].[Li]C(C)(C)C.[CH3:16][CH:17]1[CH2:22][CH2:21][O:20][C:18]1=[O:19]>C1COCC1>[OH:20][CH2:21][CH2:22][CH:17]([CH3:16])[C:18]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[Cl:10])=[O:19]
Reactant: CC1CCOC1=O
Reactant: COc1ccc(Br)c(Cl)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C)CCO)c(Cl)c1
Temperature: -85 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a 1.0 L, 3-neck round bottom flask, equipped with a mechanical stirrer and an internal thermometer, was added a solution of 4-bromo-3-chloroanisole (12.0 g, 54.0 mmol) in 350 mL of THF under nitrogen. The solution was cooled to −85° C. with a MeOH/liquid nitrogen bath. To this solution was added t-BuLi (72.0 mL, 1.6 M in pentane, 122 mmol) slowly followed by the addition of a solution of α-methyl-γ-butyrolactone (9.25 g, 92.0 mmol) in THF (30.0 mL). The internal temperature was controlled <−80° C. After 1 h stirring at <−80° C., the reaction mixture was quenched with saturated NH4Cl solution and warmed to room temperature. Water and EtOAc were added and separated. The aqueous layer was extracted with EtOAc (2×). The combined organic solutions was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (E:H, 1:3) to give 10.4 g (79%) of brown oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.6 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.85 (dd, J=8.6, 2.4 Hz, 1H), 3.88 (s, 3H), 3.77–3.69 (m, 2H), 3.64–3.56 (m, 1H), 2.16–2.07 (m, 1H), 1.76–1.67 (m, 1H), 1.23 (d, J=7.0 Hz, 3H); MS (EI m/z 241.16 (M+−H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])([CH3:11])[C:9]#[N:10].B.FC(F)(F)C(O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10]
Reactant: CC(C)(C#N)c1ccccc1Br
Agent: B
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(CN)c1ccccc1Br
Temperature: 25 °C
Yield: 60 %

Procedure:
The derivative 2-(2'-bromophenyl)-2-methylpropionitrile from Example 1/A (2.24 g; 10 mmole) was dissolved in THF (25 ml) in an inert atmosphere. A solution of borane BH3 in THF (1 M; 25 ml; 25 mmole) was slowly added to the reaction medium. The new solution obtained was refluxed for 3 h. After cooling to room temperature, an aqueous solution of trifluoroacetic acid (50 ml; 1/1) was added dropwise to the reaction mixture. The mixture was refluxed for 1 h, then the solvents were evaporated off under reduced pressure. The residue was taken up in 60 ml of hydrochloric acid HCl (10%) and washed with 3×100 ml of ethyl acetate. The aqueous phase was alkalinised (12<pH<14) then extracted with 3×50 ml of dichloromethane. The organic phases were combined, washed with 2×100 ml of a saturated NaCl solution, dried over MgSO4 then filtered. The solvent was evaporated off under reduced pressure. The desired compound was obtained as a yellowish oil.