Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:35]4[CH2:36][CH2:37][CH:32]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:33][CH2:34]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 22 %

Procedure:
4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (20 mg) was reacted with 4-(1 pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a yellow solid (22% yield). M.p. 120° C., LCMS: m/z=482.26 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.53-1.65 (m, 7H), 1.90-2.04 (m, 3H), 2.25-2.35 (m, 1H), 2.53-2.63 (m, 4H), 2.91-3.06 (m, 2H), 3.38-3.44 (m, 2H), 3.59-3.62 (m, 2H), 4.48 (s, 2H), 5.01 (bs, 1H), 6.84 (s, 1H), 7.28-7.40 (m, 9H), 7.70 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([N:24]([CH:27]([CH3:29])[CH3:28])[CH2:25][CH3:26])(C)C.CS(C)=O>O>[C:9]1([CH3:10])[CH:8]=[CH:6][CH:5]=[CH:4][C:29]=1[CH:27]1[CH2:28][CH2:26][CH2:25][N:24]1[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(N4CCCC4c4ccccc4C)n3)cc2s1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol), 2-O— tolylpyrrolidine (0.053 g, 0.33 mmol) oxalate, diisopropylethylamine (0.20 ml, 1.2 mmol) in DMSO (1.0 g, 11 mmol) was heated under CEM microwave at 140° C., 130 W (Powermax® off) for 20 min. The resultant was diluted with 5 ml of water and filtered. The solid was dried to give a brown solid (0.065 g, 46%). MS (ESI pos. ion) Found m/z: 430, (M+H)+.
Reaction SMILES: COC(=O)C.[F:6][C:7]([F:21])([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[C:8](O)=[O:9].[NH2:22][NH2:23]>CO>[F:6][C:7]([F:21])([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[C:8]([NH:22][NH2:23])=[O:9]
Reactant: O=C(O)C(F)(F)c1ccc2ncccc2c1
Reactant: NN
Solvent: CO
Solvent: COC(C)=O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of difluoro-quinolin-6-acetic acid methyl acetate (670 mg, 2.83 mmol) in methanol (20 mL) was added anhydrous hydrazine (2 mL). The mixture heated to reflux for 2 h, cooled to room temperature, concentrated and dried in high vacuum to give a light orange solid (680 mg, 100%). 1H-NMR (DMSO): δ 9.02-9.01 (1H, dd, J=1.7 Hz), 8.56-8.54 (1H, d, J=9.3 Hz), 8.28 (1H, s), 8.17-8.15 (1 H, d, J=8.8 Hz), 7.91-7.88 (1H, dd, J=2.0, 2.0 Hz), 7.66-7.63 (1H, q, J=4.0 Hz).
Reaction SMILES: C([O-])(=O)C.[Na+].C([O:9][C:10]1[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH:20]([NH:22][OH:23])[CH3:21])=[CH:12][C:11]=1[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30]>O.O1CCOCC1>[CH3:25][C:24]([C:11]1[CH:12]=[C:13]([CH:20]([N:22]([OH:23])[C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH3:21])[CH:14]=[C:15]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:10]=1[OH:9])([CH3:27])[CH3:26]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C(C)NO)cc1C(C)(C)C
Reactant: CC(C)C(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(=O)N(O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.82 g (0.01 mole) of sodium acetate in H2O (7 mL) is added to a solution of 1.07 g (0.0033 mole) of 2,6-bis(1,1-dimethylethyl)-4-[1-(hydroxyamino)ethyl]phenol acetate (Example 2) in dioxane (35 mL). Isobutyryl chloride (0.488 g, 0.00458 mole) is added dropwise and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated to half volume, diluted with H2O, and extracted with Et2O. The Et2O extracts are washed with saturated NaHCO3, brine, dried over Na2SO4, and evaporated to dryness. The residue is recrystallized from n-hexane to give white crystals, 0.62 g (56%), m.p. 147°-148.5° C.
Reaction SMILES: [OH:1][CH:2]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[C:24](Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[OH:1][C@@H:2]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:24])=[O:8]
Reactant: CCCCCCCCCCCCC#CC(O)CCCCC(=O)[O-]
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCC#C[C@H](O)CCCCC(=O)OC

Procedure:
This compound was prepared by reaction of 6-(±)-hydroxy-7-eicosynoate (preparative example V) with CBr4 /Ph3P reagent in exactly the same manner as described in preparative example VIII. Note: By use of the corresponding 6-R, and 6-S alcohols (preparative example VI) the optically active (+) and (-) 6-bromo-7-eicosanoates were also obtained
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.[I-].C([NH3+])(C)(C)C>CO>[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(S)cc1
Reactant: COC(=O)CCCCCBr
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of 4-aminothiophenol (2.4 g, 18.9 mmol) in methanol (10 mL) was added triethylamine (2.70 mL, 19.2 mmol). A solution of 6-bromohexanoic acid methyl ester (3.0 g, 18.9 mmol) and tert-butylammonium iodide (350 mg, 0.95 mmol) in methanol (5 mL) was added. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (100 mL), distilled water (100 mL) and brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by flash chromatography (2:8 to 1:1 ethyl acetate:40-60° C. petroleum ether) to give the title compound (3.0 g, 62%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](N2CCNCC2)=[CH:4][CH:3]=1.N1[NH:15][C:16](CCC(O)=O)=[C:17]2C=1C[CH2:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: Clc1ccc(C2CCNCC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(5-benzoyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)propionic acid obtained in Starting Material Synthesis Example 8 and 1-(4-chlorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Stating Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 5-benzyl-3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([N:13]1[CH2:12][CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:15][C:14]1=[O:16])(=[O:19])[CH3:18]
Reactant: COc1ccc(C2CNC(=O)O2)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C2CN(C(C)=O)C(=O)O2)cc1OC
Yield: 73 %

Procedure:
8.9 mmol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone is combined with 10 ml. of acetic anhydride and 5 ml. of pyridine and heated for 5 hours to 100°. After concentrating the reaction mixture, it is recrystallized from ethyl acetate, thus obtaining 3-acetyl-5-(3,4-dimethoxyphenyl)-2-oxazolidinone in a 73% yield, m.p. 175°-182°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:24][C:23]=2[CH:32]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[CH:20]=[CH:21][C:22]4[O:26][C:25]([C:27]5[S:28][CH:29]=[CH:30][CH:31]=5)=[N:24][C:23]=4[CH:32]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: ClCc1ccc2oc(-c3cccs3)nc2c1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: c1csc(-c2nc3cc(COc4ccc(CCCCn5ccnc5)cc4)ccc3o2)c1
Yield: 81 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 5-chloromethyl-2-(2-thienyl)benzoxazole to give 5-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)benzoxazole. The yield was 81%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 130-131° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]#[N:16])=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]#[N:16])=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(C)(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nc(C(C)(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of 1.00 g of 2-butyl-5-cyano-4-(1-hydroxy-1-methylpropyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole [prepared as described in step (a) above] and 25 ml of 20% v/v aqueous acetic acid was stirred at 60° C. for 2 hours, and then the solvent was removed by distillation under reduced pressure. The residual water and acetic acid were removed as a toluene azeotrope by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using mixtures of methanol and methylene chloride ranging from 1:9 to 1:4 by volume as the eluent, to give 0.65 g of the title compound as a glass.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([C:26](OC(C)(C)C)=[O:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[N:6]2[C:33]=1C(=O)C(Cl)(Cl)Cl)[CH3:2].I[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:4]=[C:5]2[N:6]3[C:7]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]([F:25])([F:23])[F:24])(=[O:20])=[O:21])[C:26](=[O:27])[C:33]=13)=[CH:8][CH:9]=[CH:10]2)[CH3:2]
Reactant: CCc1nc2cccc(CN(CCCCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)n2c1C(=O)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1nc2cccc3n2c1C(=O)N(CCCCCNS(=O)(=O)C(F)(F)F)C3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
To a solution of 1.73 g (2.71 mmol) of 2-ethyl-3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 15 ml of chloroform was added dropwise 0.80 ml (5.42 mmol) of iodotrimethylsilane at room temperature. The reaction mixture was stirred for 10 minutes, which was poured into ice-water, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate. This solution was extracted with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of 1.0N aqueous solution of sodium thiosulfate, then with 50 ml of a saturated aqueous saline solution. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 603 mg of the desired compound (52.3%, pale yellow solid).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([CH:10]=[O:11])=[N:6][N:7]([CH3:9])[CH:8]=1>CO>[Cl:3][C:4]1[C:5]([CH2:10][OH:11])=[N:6][N:7]([CH3:9])[CH:8]=1
Reactant: Cn1cc(Cl)c(C=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(Cl)c(CO)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of sodium borohydride (393 mg, 10.4 mmol) in methanol (25 mL) was added a solution of 4-chloro-1-methyl-1H-pyrazole-3-carbaldehyde (1.0 g, 6.9 mmol) in methanol (10 mL) at 0° C. The mixture was stirred for 4 hours at room temperature. The solvent was evaporated, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. After evaporation of the solvent, (4-chloro-1-methyl-1H-pyrazol-3-yl)methanol was obtained as a yellow oil (680 mg, 67% yield) and used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6): δ 3.77 (s, 3H), 4.34 (d, J=5.6 Hz, 2H), 5.03 (s, J=5.6 Hz, 1H), 7.85 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[C:25]([N:26]=1)=[C:24]1[CH2:27][CH:28]([CH2:30][C@H:31]3[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]3)[O:29][C:23]1=[CH:22][N:21]=2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[C:25]([N:26]=1)=[C:24]1[CH2:27][CH:28]([CH2:30][C@H:31]3[CH2:36][CH2:35][C@H:34]([NH:37][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:33][CH2:32]3)[O:29][C:23]1=[CH:22][N:21]=2
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](N)CC1)O3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)O3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (31 mg, 0.14 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexylamine (47 mg, 0.14 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by 1-hydroxybenzotriazole (24 mg, 0.16 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (32 mg, 0.16 mmol, 1.15 eq) and N,N-diisopropylethylamine (56 μL, 0.32 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexyl]-amide as a white lyophilized powder (16 mg, 21% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.C([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)C1C=CC=CC=1>C1COCC1>[OH:28][C:25]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]1
Reactant: COc1ccccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CCNCC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of 15 g of 2-bromoanisole in 50 ml of THF is cooled to -70° C., under nitrogen, a 1.6M solution of n-butyllithium in THF is added dropwise and the mixture is kept stirring for 1 hour. The mixture is cooled to -70° C. and a solution of 15.2 g of 1-benzylpiperid-4-one in 50 ml of THF is added dropwise. The mixture is kept stirring while allowing the temperature to rise to RT and after 1 hour, the reaction mixture is concentrated under vacuum. The residue is taken up in AcOEt, the organic phase washed with water, with a saturated solution of NaCl, dried over MgSO4 and the solvent evaporated under vacuum. 14 g of the expected product are obtained after crystallization from the AcOEt/ether/heptane mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH2:30][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=O>C(#N)C>[S:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:31]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])[CH:5]=[CH:4][N:3]2[CH:30]=1
Reactant: Nc1cc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)ccn1
Reactant: O=C(CBr)c1cccs1
Solvent: CC#N
Product: O=C(Nc1ccn2cc(-c3cccs3)nc2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 20.6 %

Procedure:
Compound 11 was prepared according to a process similar to that described in step 10.2, by reacting 0.1 g (0.26 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.11 g (0.53 mmol) of 2-bromo-1-(thien-2-yl)ethanone in 4 mL of acetonitrile. 0.026 g of the expected product is thus obtained in the form of a beige-coloured solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[S:11]1[CH:15]=[CH:14][N:13]=[C:12]1[NH2:16].[Na]>C1COCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][C:12]2[S:11][CH:15]=[CH:14][N:13]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1nccs1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Na]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Nc2nccs2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A solution of 2-chloro-5-nitropyridine (8.4 g, 53 mmol) and thiazol-2-amine (7.6 g, 76 mmol) in THF (250 mL) is cooled to 0° C. Sodium tert-butoxyde (30% w/w THF, 80 mL) is the added slowly over 15 minutes. The reaction mixture is then warmed slowly to room temperature and stirred 16 hours. The reaction mixture is then poured into a mixture of 1/1 ice/water (1.2 L) with stirring. The solid is filtered and air dried to give a powder (9.74 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.17 (d, J=9.35 Hz, 2H), 7.20 (d, J=3.54 Hz, 1H), 7.49 (d, J=3.54 Hz, 1H), 8.43 (dd, J=9.35, 2.78 Hz, 1H), 9.15 (d, J=2.78 Hz, 1H), 12.17 (s, 1H). LCMS (M+H)+: 223.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([CH2:41]O)[CH:38]=[CH:39][CH:40]=1>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH2:41][C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=1)=[O:11])[CH2:3]2
Reactant: O=C(O)C1CN2CCC1CC2
Reactant: OCc1cccc(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1cccc(F)c1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (95 mg, 0.50 mmol), EDC (143 mg, 0.74 mmol), HOBT (114 mg, 0.74 mmol), and triethylamine (242 μl, 1.73 mmol) were dissolved in dry THF (5 ml). (3-Fluorophenyl)methanol (68.8 mg, 0.54 mmol) was dissolved in dry THF (2 ml) and added to the reaction mixture. The resulting reaction was stirred at room temperature overnight. The volatiles were evaporated, and the crude was taken up with EtOAc and washed with water and then with sat. NaHCO3. The organic phase was separated, dried over sodium sulfate, filtered, and evaporated under vacuum to obtain 3-fluorobenzyl quinuclidine-3-carboxylate (120 mg, racemic mixture). The compound was used in the next step without any further purification.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][N:18]=1)[C:14]#[N:15]>>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([S:1][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][N:18]=2)[C:14]#[N:15])[CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: OCc1cccc(S)c1
Product: N#Cc1ccnc(Sc2cccc(CO)c2)c1
Yield: 62.9 %

Procedure:
Using the method of Preparation 155 using (3-mercaptophenyl)methanol (6.00 g, 42.8 mmol) and 2-chloroisonicotinonitrile (5.65 g, 40.8 mmol) affords the title compound (6.22 g, 63%): 243 (M+H, 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[CH3:18][C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH:28][C:29]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)=[O:30])=[CH:23][CH:22]=2>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:35]([C:34]3[CH:33]=[CH:32][C:31]([C:29]([NH:28][C:24]4[CH:25]=[C:26]5[C:21](=[CH:22][CH:23]=4)[NH:20][C:19]([CH3:18])=[CH:27]5)=[O:30])=[CH:38][CH:37]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: Cc1cc2cc(NC(=O)c3ccc(C=O)cc3)ccc2[nH]1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5[nH]c(C)cc5c4)cc3)[nH]c2c1

Procedure:
Compound 662 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(2-methyl-5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C26H24N4O3: 441.18; found: 441.02.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:9]/[CH:10]=[CH:11]/S(C)(=O)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[I-:16].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][I:16])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: [I-]
Reactant: COC1(C/C=C/S(C)(=O)=O)CCOCC1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC1(/C=C/CI)CCOCC1
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
To a 0° C. solution in acetone of 4-methoxy-4-(3-methanesulfonyl-trans-prop-2-enyl)tetrahydropyran (505 mg, 2.02 mmol), prepared as in step 5 was added sodium iodide (605 mg, 4.03 mmol), and the reaction was stirred for 15 min. The reaction was partitioned between ethyl acetate and brine. The organic layer was washed twice with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 4-methoxy-4-(3-iodo-trans-propenyl)tetrahydropyran (550 mg, 97%) as a dark yellow oil. The iodide was of sufficient purity to use without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH2:19]O)=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)Br.[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:31]=CC=C[CH:27]=1.C([Mg]Br)C=C>ClCCl.O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([CH2:19][CH2:31][CH:26]=[CH2:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc2ncccc2c1OCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrC(Br)(Br)Br
Agent: C=CC[Mg]Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCCc1ccc2ncccc2c1OCc1ccccc1

Procedure:
Treatment of [5-(benzyloxy)quinolin-6-yl]methanol with carbontetrabromide and triphenylphosphine in dichloromethane and subsequent treatment with allyl magnesiumbromide in tetrahydrofu ran following the procedure described for Example 1, step 1 provides 5-(benzyloxy)-6-but-3-enylquinoline.