Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][CH2:8][N:7]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:5])[CH3:2].B.[O:29]1CCCC1>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([OH:29])[CH2:8][N:7]1[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(c2ccc(OC)cc2)=CCN1c1ccc(OC)cc1
Reactant: C1CCOC1
Agent: B
Product: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](O)CN1c1ccc(OC)cc1
Temperature: 40 °C

Procedure:
To a stirred solution of 19.5 g of (S)-1,4-bis-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid ethyl ester in 400 ml of tetrahydrofuran are added 56 ml of a solution of borane-tetrahydrofuran (1M) at room temperature. The reaction mixture is heated to 40° C. for 2-6 hours, cooled to room temperature, and quenched by the addition of 50 ml of 2N sodium hydroxide solution and 100 ml of 30% hydrogen peroxide solution. The organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow solid. Rf=0.33 (EtOAc-heptane 1:1); Rt=3.58.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[N:13]2[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]2)=[CH:7][C:6]=1[C:14](OC)=[O:15])=O.[NH2:20][NH2:21]>C(O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[C:5]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[C:14](=[O:15])[NH:21][N:20]=1
Reactant: COC(=O)c1cc2ccccn2c1C(=O)C(F)(F)F
Reactant: NN
Solvent: CCO
Product: O=c1[nH]nc(C(F)(F)F)c2c1cc1ccccn12
Yield: 79 %

Procedure:
A mixture of (I) (3.60 g, 13.3 mmol) and excess 85% aqueous hydrazine in ethanol (250 mL) was heated under reflux for 10 minutes (a precipitate formed). After cooling in a freezer overnight, the solid was collected by filtration and dried to give 4-trifluoromethylpyridazino[4,5-b]indolizin-1-one (II, 2.65 g, 79%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:39]=[CH:38][C:15]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[C:21]3[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)=[O:17])=[CH:14][CH:13]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][CH2:29][C:21]1[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([C:16]([C:15]3[CH:38]=[CH:39][C:12]([Cl:11])=[CH:13][CH:14]=3)([OH:17])[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:19]=2)[NH:24][C:23](=[O:28])[CH:22]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(CCc3cccc(Cl)c3)c2c1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=c1cc(CCc2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole (201 mg, 2.368 mmol, 4.00 equip) in THF (10 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 1.495 mL, 2.392 mmol, 4.04 equip) dropwise. After 30 minutes, a solution of 6-(4-chlorobenzoyl)-4-(3-chlorophenethyl)quinolin-2(1H)-one (250 mg, 0.592 mmol, 1 equip, prepared as described in ANGIBAUD, P. R., et al., PCT Publication WO2002/051835 A1, published 4 Jul. 2002) in HMPA (4 mL) was added dropwise and the reaction mixture was warmed to room temperature. The reaction was stirred overnight, then quenched with water and the resulting mixture extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by MPLC using methanol-dichloromethane as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[CH2:20]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:20][CH3:21])=[CH:31][CH:30]=1
Reactant: CCOc1ccc(C(=O)O)cc1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
In a reaction vessel were placed 0.29 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.12 g of 4-ethoxybenzoic acid, 0.12 g of potassium carbonate and 10 ml of N,N-dimethylformamide, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.30 g of 3,5-dichloro-4-(3-(4-ethoxybenzoyloxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy)-benzene (86% yield), nD24.0 1.5715.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:17])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][S:7]([C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:38])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2cccc3ccccc23)C2C(=O)CC2C1
Solvent: ClCCl
Product: CC(=O)NCCS(=O)C1=C(C(=O)OCc2cccc3ccccc23)C2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 60 mg of 3-(2'-acetamidoethylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, 1-naphthylmethyl ester, in 10 mL of methylene chloride at -50° under argon was added a solution of 32 mg of m-chloroperbenzoic acid in 3 mL of methylene chloride in one portion. This solution was stirred for 30 min at -40° and then allowed to warm to room temperature over a 30 min period. The methylene chloride solution was washed sequentially with aqueous sodium sulfite and aqueous sodium bicarbonate (2X), dried over sodium sulfate and evaporated to dryness. The crude product was purified by preparative thin layer chromatography on a 20×20×0.2 cm silica gel plate, eluted with 5% methanol in methylene chloride, to afford 55 mg (88%) of 3-(2'acetamidoethylsulfinyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, 1-naphthylmethyl ester, as a glassy mixture of 2 diastereoisomers (at sulfur). IR (Nujol mull): 3250, 1785, 1715, 1670 cm-1 ; NMR (220 MHz; CDCl3): δ 1.93 (3H, s), 2.8-3.7 (9H, m), 4.66 (1H, m), 5.5-5.75 (2H, m), 6.48 (1H, m), and 7.3-1.1 (7H, m); MS (field desorption) confirmed molecular weight of 425. ##STR23##
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=O)[CH3:12].Cl.[CH3:15][N:16](C)[NH2:17]>C(O)C>[CH3:15][N:16]1[C:2]2[C:3](=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[C:11]([CH3:12])=[N:17]1
Reactant: CN(C)N
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: CCO
Product: Cc1nn(C)c2ccc([N+](=O)[O-])cc12
Yield: 627.7 %

Procedure:
To a solution of 1-(2-chloro-5-nitrophenyl)ethanone (500 mg, 2.5 mmol) in anhydrous ethanol (15 mL) was added 1,1-dimethylhydrazine hydrochloride (3.38 g, 35.0 mmol) under nitrogen protection. The mixture was heated at reflux for 10 h and evaporated under reduced pressure to afford crude 307a (3.0 g), which was used in the next step without further purification. MS-ESI: [M+H] 192.2
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[CH3:14][C:15]1[C:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][CH:3]=2)=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)cc2)o1

Procedure:
Example 34 was prepared using 2-(4-iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and N-[4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 27) with propan-2-ol as the solvent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]2[C:12](=[O:17])[NH:13][NH:14][C:15]=2[CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)(=O)C>[C:18]([N:14]1[C:15]([CH3:16])=[C:11]([CH2:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C:12]([OH:17])=[N:13]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Cc2c(C)[nH][nH]c2=O)cc1F
Solvent: CC(=O)O
Product: COc1ccc(Cc2c(O)nn(C(C)=O)c2C)cc1F
Temperature: 135 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
A mixture of 1,2-dihydro-4-[(3-fluoro-4-methoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (synthesized as described in WO0236602; 4.11 g, 0.0174 mol), acetic anhydride (41 mL) and acetic acid (41 mL) was stirred at 135° C. for 8 hours and at room temperature for 12 hours. After being concentrated, the reaction mixture was diluted with toluene and then concentrated again. To the resulting residue, methanol (400 mL) and a 25 wt % methanol solution of sodium methoxide (0.37 mL) were added and stirred for 20 hours. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1) to give 1-acetyl-4-[(3-fluoro-4-methoxyphenyl)methyl]-3-hydroxy-5-methyl-1H-pyrazole (960 mg, 20%) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([F:33])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:26]([F:33])[CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cncnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1)c1cncnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyrimidine-5-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B-(4-chloro-2-fluorophenyl)-boronic acid (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 92.2%, 425.0446 (M−H)−.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH:6]=[CH:7][N:8]=1.[C:18]1([CH:25]=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=1)[OH:19].C([O-])([O-])=O.[K+].[K+].Cl>O.CS(C)=O>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([Cl:16])[CH:13]=1)[CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:3][O:19][C:18]1[CH:20]=[C:21]([OH:22])[CH:23]=[CH:24][CH:25]=1
Reactant: ClCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Oc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.7 %

Procedure:
To a mixture of 2-chloromethyl-1-(3,5-dichlorobenzyl)-1H-imidazole hydrochloride (156 mg, 0.5 mmol), resorcinol (330 mg, 3.0 mmol) and DMSO (1 mL) was added K2CO3 (691 mg, 5.0 mmol). The reaction was stirred at ambient temperature for 14 h before diluting with water (20 mL). A solution of 1N HCl was added until the mixture was made only slightly basic (pH 8) before extracting with EtOAc (30 mL). The EtOAc phase was washed with water (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:2 to 1:3 hexane/EtOAc then 100% EtOAc) to provide the title compound (113 mg, 65%) as an off-white solid: ESI MS m/z 349 [C17H14Cl2N2O2+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[N:11][C:10]=2[NH2:20].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[N:11][C:10]=2[NH2:20]
Reactant: [H][H]
Reactant: COC/C=C/c1cnc2c(N)nc3ccccc3c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCCc1cnc2c(N)nc3ccccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of (E)-2-(3-methoxyprop-1-enyl)benzo[f][1,7]naphthyridin-5-amine (Example 34) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and the crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-(3-methoxypropyl)benzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (CDCl3): δ 8.64 (d, 1H), 8.46 (d, 1H), 8.19 (d, 1H), 7.66 (d, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 6.56 (bs, 2H), 3.37 (t, 2H), 3.31 (s, 3H), 2.91 (t, 2H), 1.93-2.00 (m, 2H). LRMS [M+H]=268.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:50]([O:52][C@@H:53]([CH2:59][C:60]1[CH:65]=[CH:64][C:63](O)=[CH:62][CH:61]=1)[C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH3:51]>>[CH2:57]([O:56][C:54](=[O:55])[C@@H:53]([O:52][CH2:50][CH3:51])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)\[CH3:18])=[CH:62][CH:61]=1)[CH3:58]
Reactant: C/C(=C\CO)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)cc1)OCC
Yield: 34.4 %

Procedure:
The title compound was prepared from (E)-3-(4′-bromo-biphenyl-4-yl)-but-2-en-1-ol (0.364 g, 1.2 mmol), triphenylphosphine (0.328 g, 1.3 mmol), diethyl azodicarboxylate (0.173 ml, 1.1 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.238 g, 1.0 mmol) by a procedure analogous to that described in example 1c, yielding 0.180 g (34%) of (E)-(S)-3-{4-[3-(4′-bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][C:13]1[CH:17]=[C:16]([C@H:18]([OH:20])[CH3:19])[O:15][N:14]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([NH2:9])=[C:2]([O:20][C@@H:18]([C:16]2[O:15][N:14]=[C:13]([CH3:12])[CH:17]=2)[CH3:19])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Cc1cc([C@@H](C)O)on1
Product: Cc1cc([C@@H](C)Oc2cc(F)ccc2N)on1

Procedure:
Yield: 0.7 g (33%), ESI-MS: m/z=128 (M+H)+, Rt(HPLC): 0.28 min (HPLC-G) III.5 was prepared in a similar manner as the racemate intermediate III.4 from 2,4-difluoro-1-nitro-benzene and (1R)-1-(3-methylisoxazol-5-yl)ethanol.
Reaction SMILES: [Na].C1(C)C=CC(S([C:11]2[N:12]=[C:13]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]3=[N:15][CH:16]=2)(=O)=O)=CC=1.[CH2:27]([OH:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:27]([O:33][C:11]1[N:12]=[C:13]2[CH:19]=[N:18][N:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]2=[N:15][CH:16]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Cc1ccc(S(=O)(=O)c2cnc3c(cnn3-c3ccccc3)n2)cc1
Reactant: CCCCCCO
Agent: [Na]
Product: CCCCCCOc1cnc2c(cnn2-c2ccccc2)n1
Yield: 90 %

Procedure:
In 50 ml of hexanol was dissolved 2.1 g (0.091 mole) of metallic sodium, and then, 14.6 g (0.043 mole) of 5-(4-tolylsulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyrazine was added to the solution. The mixture was heated under reflux for 2 hours. After completion of the reaction, the exessive amount of hexanol was removed by distillation under a reduced pressure. The residue was washed with water, dried and then recrystallized from a benzene/methanol (1:2) mixed solvent to obtain 11.5 g (the yield was 90%) of 5-hexyloxy-1-phenyl-1H-pyrazolo[3,4-b]pyrazine in the form of a colorless needle crystal.
Reaction SMILES: [Br:1][C@@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.C(OCC)(=O)C.[CH3:17][NH:18][CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[OH:7][C@@H:8]1[C@@H:2]([Br:1])[CH2:3][CH2:4][C@H:5]([C:6]([N:18]([CH3:19])[CH3:17])=[O:10])[CH2:9]1
Reactant: O=C1O[C@H]2C[C@@H]1CC[C@@H]2Br
Reactant: CNC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)[C@H]1CC[C@H](Br)[C@@H](O)C1
Temperature: 5 °C
Reaction time: 14 h

Procedure:
(1S,4S,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (200 g) was added to ethyl acetate (1000 ml), and the obtained solution was then cooled to 5° C. Thereafter, a 50% dimethylamine aqueous solution (305.7 ml) was added to the reaction solution, and the obtained mixture was then stirred for 14 hours. Thereafter, a mixed solution of citric acid (131.17 g), common salt (92.00 g) and water (324 ml) was added to the reaction solution, and the obtained mixture was then heated to 30° C. The reaction solution was stirred for 30 minutes, and thereafter, it was left at rest, so that the organic layer was separated. Further, the aqueous layer was extracted with ethyl acetate (800 ml) again. The organic layers were gathered, and the gathered organic layer was then concentrated to 1000 ml. Water (400 ml) was added to the concentrated solution, and the thus mixed solution was concentrated again to obtain an aqueous solution (500 ml) of (1S,3S,4S)-3-hydroxy-4-bromo-N,N-dimethylcyclohexanecarboxamide. To this aqueous solution (500 ml), a 28% ammonia aqueous solution (1247 ml) and a 25% sodium hydroxide aqueous solution (123 ml) were added, and the obtained solution was then heated to 40° C., followed by stirring the reaction solution for 6 hours. Thereafter, the reaction solution was concentrated to 1000 ml to obtain an aqueous solution containing the title compound (147.52 g, yield: 81%).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]([CH:8]1[C:12](=O)[CH2:11][O:10][CH2:9]1)=[O:7].OS(O)(=O)=O>O.CCOCC>[CH3:4][O:5][C:6]([CH:8]1[CH:12]([C:1]#[N:2])[CH2:11][O:10][CH2:9]1)=[O:7]
Reactant: [C-]#N
Reactant: COC(=O)C1COCC1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1COCC1C#N
Reaction time: 16 h

Procedure:
To a stirred solution of 3.9 g (60 mmol) KCN in 5.5 ml of water at 4° C., a solution of 2.9 g (20 mmol) of 4-oxo-tetrahydro furane 3-carboxylic acid methyl ester in ether (26 ml) was added. To the precipitate of salts, 3.5 ml H2SO4 (18 N) was added and stirred for 16 hours. Then the organic solution was separated, the salts were washed twice with benzene, dried over sodium sulfate and concentrated in vacuo to give 4-cyano-tetrahydro furane 3-carboxylic acid methyl ester.
Reaction SMILES: C([Sn](CCCC)(CCCC)/[CH:6]=[CH:7]\[O:8][CH2:9][CH3:10])CCC.Br[C:20]1[C:21]([NH:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[N:22][C:23]([Cl:26])=[N:24][CH:25]=1>CC#N.[N+](CC)(CC)(CC)CC.[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:26][C:23]1[N:22]=[C:21]([NH:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:20](/[CH:6]=[CH:7]\[O:8][CH2:9][CH3:10])=[CH:25][N:24]=1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: CCO/C=C\c1cnc(Cl)nc1NC(CC)CC
Temperature: 100 °C

Procedure:
To a solution of tributyl-((Z)-2-ethoxy-vinyl)-stannane (4.25 g, 8.8 mmol) in CH3CN (10 mL) is added (5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (2.25 g, 8 mmol), Et4NCl (1.33 g, 8 mmol) and Pd(PPh3)2Cl2 (280 mg, 0.4 mmol) at ambient temperature. The reaction mixture is purged with N2, sealed in a microwave reactor and heated at 100° C. for 20 min. After cooling to room temperature, the mixture is concentrated in vacuo and the residue is purified by flash chromatography (SiO2, EtOAc/hexane 5:95 to 40:60) to give [2-Chloro-5-((Z)-2-ethoxy-vinyl)-pyrimidin-4-yl]-(1-ethyl-propyl)-amine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][NH:25][C:26]1[C:27]([CH3:41])=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][C:27]([CH3:41])=[C:26]([NH:25][CH3:24])[CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Product: CNc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and methyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 163.1.1) to give the title compound as a white solid. (HPLC: tR 2.10 min (Method A); M+H=414 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.12-8.06 (m, 2H), 7.96-7.92 (m, 1H), 7.89-7.87 (m, 1H), 7.62-7.60 (m, 1H), 6.73-6.70 (m, 1H), 5.51 (q, br, 1H), 3.88 (s, 3H), 3.57 (s, 3H), 2.80 (d, 3H), 2.31 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [Li]c1ccccc1
Reactant: BrCCCCCCCBr
Solvent: C1CCOC1
Product: BrCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a stirred solution of 1,7-dibromoheptane (49 g, 0.18 mol) (Aldrich) in THF (300 ml), at -30° C. to -40° C., under N2, was added, dropwise, during 3 h, a solution of phenyllithium (15 g, 0.18 mol) in cyclohexane-ether (2.0 M solution, Aldrich). The reaction was allowed to stir at -10° C. to -20° C. for 3 h and at room temperature overnight. After slow, careful dilution with H2O (50 ml), the aqueous layer was extracted with Et2O (2×150 ml). The extracts and the organic layer were combined, dried (Na2SO4) and concentrated to a yellow oil. Distillation through a Vigreaux column provided 22.5 g of 1-bromo-7-phenylheptane, bp 84°-88° C. (0.2 mm), nD24 1.5220.