Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH2:28]([N:30]([CH2:40][CH3:41])[CH2:31][C:32]1[N:33]=[C:34]([N+:37]([O-])=O)[NH:35][CH:36]=1)[CH3:29].CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[CH2:28]([N:30]([CH2:31][C:32]1[N:33]=[C:34]([NH:37][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[F:27])=[CH:14][CH:15]=2)=[O:5])[NH:35][CH:36]=1)[CH2:40][CH3:41])[CH3:29]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CCN(CC)Cc1c[nH]c([N+](=O)[O-])n1
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)Cc1c[nH]c(NC(=O)c2ccc(-c3c(F)c(OC)cc(OC)c3F)c3nccnc23)n1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture at 70° C. for 7 h and using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1). Diethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 18.1) instead of 2-nitroimidazole was used in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. Title compound: ESI-MS: 497.0 [M+H]+; tR=3.36 min (System 1); TLC: Rf=0.18 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [Cl:1]NC(=O)CCC(N)=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH:22]([C:27]2[CH:44]=[CH:43][C:30]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH:20]=[O:21])=[CH:14][CH:13]=1>C(#N)C>[Cl:1][C:17]1[CH:16]=[C:15]([CH:18]([CH:22]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])=[CH:43][CH:44]=2)[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH:20]=[O:21])[CH:14]=[CH:13][C:12]=1[O:11][CH3:10]
Reactant: NC(=O)CCC(=O)NCl
Reactant: CCCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(CC=O)c1ccc(OC)cc1
Solvent: CC#N
Product: CCCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(CC=O)c1ccc(OC)c(Cl)c1

Procedure:
N-Chlorosuccinamide (40 mg, mmol) was added to an acetonitrile solution (2 ml) containing enantiopure tert-butyl N-(4-{1-[1-(4-methoxyphenyl)-3-oxopropyl]pentyl}benzoyl)-β-alaninate (20 mg, 0.42 mol), which was prepared following the procedure described in Example 1. The solution was then heated in a screw cap tube for 35 minutes at 85° C. The solution was concentrated and the residue purified by PTLC using an EtOAC/hexanes eluent to give a mixture of compounds containing the title compound and the corresponding 3,5-diCl analog (˜30% by NMR). LC1 4.00 min. (M+H) 460, di Cl LC1 4.15 min. (M+H) 494 selected data 1H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H); 7.72 (d, J=8.2 Hz, 2H); 7.23-7.15 (m, 3H); 6.86 (d, J=8.4 Hz, 2H); 3.88 (S, 3H); 3.68 (q, J=5.9 Hz, 2H); 3.29-3.23 (m, 1H); 2.75-2.65 (m, 1H); 2.56-2.50 (m, 2H); 2.39-2.31 (m, 1H); 1.46 (s, 9H); 0.66 (t, 3H).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=398.6 (M+H+), was prepared in accordance with the general method 8 of example 49 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 4-fluorobenzoyl chloride.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[CH:24]=[C:23]2[C:18]([C@H:19]([OH:32])[C@@H:20]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][O:22]2)=[CH:17][CH:16]=1)C.[OH-].[Na+]>C(O)(C)C.O.C(OC(C)C)(C)C>[CH2:25]([C@@H:20]1[C@@H:19]([OH:32])[C:18]2[C:23](=[CH:24][C:15]([C:6]3[CH:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=[CH:10][C:5]=3[C:4]([OH:33])=[O:3])=[CH:16][CH:17]=2)[O:22][CH2:21]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: O=C(O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
A mixture of (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid ethyl ester (897 g, 1.93 mol) and 10% aqueous sodium hydroxide (980 mL, 2.72 mol) in isopropyl alcohol (9 L) was heated at reflux for 6 hours, cooled to ambient temperature, and stirred for 12 hours. The reaction mixture was diluted with water (13.5 L), hexanes (9 L), and isopropyl ether (4.5 L). The aqueous layer was separated and extracted with hexanes (9 L) and isopropyl ether (4.5 L), adjusted to pH 2 with 2N aqueous hydrochloric acid, and extracted with ethyl acetate (8 L and 4 L). The combined ethyl acetate extracts were washed with water (6 L), dried over magnesium sulfate, and concentrated in vacuo to a dark amber oil which was diluted with toluene (2 L) and concentrated again to an oil. The oil was dissolved in toluene (4.2 L) at 60° C., and hexanes (8.8 L) were added at a rate to maintain a temperature of greater than 50° C. The tan solids which precipitated upon slowly cooling to ambient temperature over several hours were filtered and washed with 2:1 hexane/toluene (2 L). These solids were dissolved in toluene (5 L) at 60° C., treated with Darco® G-60, filtered, washed with toluene, and concentrated in vacuo to approximately 4.0 L. This mixture was heated to 50-60° C., treated drop-wise with hexanes (8.6 L), cooled, and granulated at 5° C. for 1 to 2 hours. The resulting solids were filtered, washed with 2:1 hexanes/toluene (2 L), and the wet cake was stirred with hexanes (4 L) at reflux for 30 minutes. This mixture was cooled to ambient temperature, granulated for 1 hour, filtered, and the resulting solids were dried under vacuum overnight to provide 450 g (55%) of (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid as an off white solid: 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.1 Hz, 1H), 7.66 (dd, J=1.1, 8.1 Hz, 1H), 7.63 (s, 1H), 7.15-7.32 (m, 6H), 6.89 (dd, J=1.7, 7.9 Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 6.1 (bs, 2H), 4.50 (d, J=4.3 Hz, 1H), 4.18 (dd, J=2.7, 11.2 Hz, 1H), 3.94 (dd, J=4.6, 11.0 Hz, 1H), 2.74 (dd, J=6.1, 13.8 Hz, 1H), 2.51 (dd, J=9.4, 13.9 Hz, 1H),2.22(m, 1H); IR 3454, 3218 (br), 1699, 1431, 1337, 1299, 1275, 1258, 1191, 1178, 1135, 1123, 700 cm-1 ; mp 142° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)(=O)C.[OH-].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C1COCC1.O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:11]1
Reactant: CC(=O)OCCCCCC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCC(CCCCCO)C1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 5-(3-piperidinyl)-1-pentanol acetate (7.37 g, 31.9 mmol) in THF (50 ml) was added a solution of potassium hydroxide (5.36 g, 96 mmol) in water (30 ml) and the mixture was stirred in an ice-water bath. To this was added a solution of benzyl chloroformate (5.00 ml, 35.0 mmol) in THF (25 mL) dropwise over a period of 40 mins. After stirring in the cold bath for 30 mins., the mixture was allowed to warm to rt and stirred for 5 hours. The organic solvent was removed by evaporation in vacuo and the aqueous phase was diluted further with water (75 ml) and extracted with EtOAc (3×100 ml). The combined organic extracts was washed with saturated NaCl solution (100 ml), separated, dried (Na2SO4), filtered the solvent evaporated in vacuo and the residue was purified by column chromatography. The sample was loaded in dichloromethane and purified on silica (Si) 2×100 g cartridges using a gradient of 0-100% ethyl acetate in cyclohexane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (6.50 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:13]2([C:18]#N)[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.FC(F)(F)C1C=CC(C2(C=[O:36])CCCC2)=CC=1>>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:13]2([CH:18]=[O:36])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: N#CC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: O=CC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1

Procedure:
1-(3,5-bis(trifluoromethyl)phenyl)cyclopentanecarbaldehyde (456) was synthesized as a colourless liquid from 1-(3,5-bis(trifluoromethyl)phenyl)cyclopentanecarbonitrile (455) following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbaldehyde (238).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N+:23]([O-])=O)=[C:11]([CH:26]=[CH:27]N(C)C)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]1[NH:10][C:11]2=[CH:26][CH:27]=[N:23][C:12]2=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=Cc1nc(OCc2ccccc2)nc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: c1ccc(COc2nc(OCc3ccccc3)c3nccc-3[nH]2)cc1
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Zinc dust (30 g) was added to a solution of the product from Example 36.2 (20 g) in acetic acid (300 ml) with cooling to control the exotherm. The resulting mixture was then stirred for 2 h, filtered, and the filtrate was concentrated to dryness. The residue was partioned between chloroform and aqueous sodium bicarbonate, the organic layer was dried and then concentrated to dryness to give a solid residue of 2,4-dibenzyloxypyrrolo[3,2-d]pyrimidine (15.2 g).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([NH:15][CH2:16][CH2:17][NH2:18])C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:13][NH:15][CH2:16][CH2:17][NH:18][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCNCCN
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CNCCNc1cc([N+](=O)[O-])ccc1C#N
Reaction time: 16 h

Procedure:
A mixture of 2-fluoro-4-nitrobenzonitrile (13.2 g), N-ethylethylenediamine (16 mL) and potassium carbonate (10 g) in acetonitrile (250 mL) was vigorously stirred for 16 hours resulting in the formation of an orange solid. The mixture was diluted with water and filtered. The precipitate was washed with water and dried to provide 2-(2-methylamino-ethylamino)-4-nitro-benzonitrile (10 g): 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H), 7.55 (m, 2H), 5.8 (br, 1H), 3.4 (q, 2H), 3.1 (m, 2H), 2.8 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[CH:4][NH:3]1.Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=1>>[CH3:37][N:35]1[CH:36]=[C:32]([CH2:31][N:3]2[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=4)=[C:14]([CH:17]=3)[C:15]#[N:16])=[N:7][C:2]2=[O:1])[CH:33]=[N:34]1
Reactant: Cn1cc(CCl)cn1
Reactant: N#Cc1cc(CCc2cc[nH]c(=O)n2)ccc1Oc1cccc(C(F)(F)F)c1
Agent: Cl
Product: Cn1cc(Cn2ccc(CCc3ccc(Oc4cccc(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1

Procedure:
The title compound was prepared with a procedure similar to that described for E1 starting form 5-[2-(2-oxo-1,2-dihydro-4-pyrimidinyl)ethyl]-2-{[3-(trifluoromethyl)phenyl]oxy}-benzonitrile and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 480 [M+H]+; 2.90 min (ret time).
Reaction SMILES: [CH:1]1([N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[C:19]([F:27])[CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:27])[CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C(=O)O)c(F)c1)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reaction time: 40 h

Procedure:
A solution of methyl 4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]-2-fluorobenzoate (Intermediate 25, 85 mg; 0.20 mmol) in THF (5 ml) and MeOH (5 ml) was treated with an aqueous solution (5 M) of sodium hydroxide (198 μl; 0.99 mmol). After stirring for 40 hours, HCl 1 N was added until pH 3, then the solution was concentrated under vacuum, AcOEt was added and the organic layer was washed with brine, dried (MgSO4) and removed under vacuum to afford an oily residue which was purified by preparative HPLC to give the title compound as an amorphous white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:26](=[O:27])[C:11]3=[CH:12][NH:13][C:14]([CH3:25])=[C:15]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:26](=[O:27])[C:11]3=[CH:12][NH:13][C:14]([CH3:25])=[C:15]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:20])[CH:17]=4)[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(C(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a solution of 3-[2-(4-chlorophenyl)-3,5-dihydro-6-methyl-3-oxo-2H-pyrazolo[4,3-c]pyridin-7-yl]benzoic acid (65 mg, 0.171 mmol) in anhydrous N,N-dimethylacetamide (2 ml) was added pyrrolidine (15.7 ml, 0.188 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (48.0 mg, 0.188 mmol), then, dropwise, anhydrous triethylamine (52.5 ml, 0.376 mmol). The mixture was stirred under nitrogen at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 3-5% MeOH/CH2Cl2) to give 63.2 mg (85%) of the title compound as a yellow solid; mp 253-255° C.; 1H NMR (360 MHz, DMSO-d6) δ1.85 (4H, m), 2.29 (3H, s), 3.49 (4H, br q, J 6.9 Hz), 7.41 (2H, d, J 9.0 Hz), 7.55-7.59 (3H, m), 7.66 (1H, s), 8.12 (2H, d, J 9.0 Hz), 8.58 (1H, s), 12.49 (1H, br s); MS (ES+) m/z 433/435 [H]+. Anal. found: C, 63.85; H, 4.96; N, 12.33. C24H21ClN4O2.H2O requires: C, 63.93; H, 5.14; N, 12.42%.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[N+:12]([CH3:15])([O-:14])=[O:13].[O-]CC.[Na+]>C(O)C>[N+:12]([CH2:15][C:7]1([OH:10])[CH2:6][CH2:5][C:4]2([O:3][CH2:2][CH2:1][O:11]2)[CH2:9][CH2:8]1)([O-:14])=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 120 h
Yield: 40 %

Procedure:
To a solution of 1,4-cyclohexanedione mono-ethylene ketal (30.0 g, 192 mmol) and nitromethane (15.6 mL, 288 mmol) in ethanol (18 mL) was added a solution of sodium ethoxide in ethanol (2.67 M, 3.4 mL, 9.6 mmol). The solution was stirred at room temperature (rt) for 5 days (d), then was concentrated under reduced pressure to a brown oil that was partitioned between water (100 mL) and dichloromethane (100 mL). The aqueous layer was extracted with dichloromethane (3×100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to a light brown oil. Purification by flash chromatography (silica gel, 40% ethyl acetate/hexanes) provided the product 8-(nitromethyl)-1,4-dioxaspiro[4.5]decan-8-ol as a clear oil (16.7 g, 40%) that slowly formed clear crystals overnight.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9].[C:10]1([CH3:19])[C:11]([C:16](Cl)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:16]([C:11]2[C:10]([CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:17])=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9]
Reactant: Cn1cccc1CC#N
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1ccc(CC#N)n1C

Procedure:
To a solution of 24 g. (0.20 mole) of 1-methylpyrrole-2-acetonitrile and 30.92 g. (0.20 mole) o-toluoyl chloride in 200 ml. methylene chloride (cooled externally to -20° C.) is added dropwise 23.4 ml. (0.20 mole) of stannic chloride. After the addition is complete, the yellow mixture is permitted to come to room temperature. The mixture is then poured into ice-dilute hydrochloric acid. The two phases are separated. The organic phase is washed consecutively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid, and saturated sodium chloride solution; dried over magnesium sulfate; and the product, 1-methyl-5-(o-toluoyl)-pyrrole-2-acetonitrile, is separated from the residual oil by chromatography. The column is packed with acid washed alumina in hexane. The eluant is benzene. The product is found in the first compound bearing fraction as determined by ultraviolet absorption at 260 mμ. The benzene is evaporated and the resultant solid is purified by recrystallization twice from methanol, m.p. 90-92.5° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:26]4[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C(C)(C)C)cc4)cc3CC[C@@H]12
Yield: 69.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-t-butylphenylboronic acid (139 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 163 mg (69%) of the title compound as an amorphous solid. mp 141°-147°. FDMS: m/e=361 α[D]589 =+67.88 (c=1.05, chloroform).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][N:5]([S:25]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)(=[O:27])=[O:26])[C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH3:22])[C:11]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[N:12][C:8]=2[CH:7]=1.[ClH:39].C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[ClH:39].[ClH:39].[CH3:38][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([S:25]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)(=[O:26])=[O:27])[C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH3:22])[C:11]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH2:44])=[NH:19])=[CH:20][CH:21]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: CN(C)CCN(c1ccc2c(c1)nc(Cc1ccc(C#N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CN(C)CCN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1e from 4-[(5-(N-(2-dimethylamino-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[CH3:16][C:17]1[S:18][C:19]([C:28](O)=[O:29])=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1>>[CH3:16][C:17]1[S:18][C:19]([C:28]([N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:1]2[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:29])=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1
Reactant: Cc1nc(-c2ccccc2)c(C(=O)O)s1
Reactant: CCOC(=O)CC1NCC2CCCCC21
Product: CCOC(=O)CC1C2CCCCC2CN1C(=O)c1sc(C)nc1-c1ccccc1

Procedure:
Ethyl 2-(2-(2-methyl-4-phenylthiazole-5-carbonyl)octahydro-1H-isoindol-1-yl)acetate was prepared according general procedure A from ethyl 2-(octahydro-1H-isoindol-1-yl)acetate and 2-methyl-4-phenylthiazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][SiH:2]([Cl:4])[Cl:3].[CH3:5][CH:6]([CH3:10])[CH2:7][CH:8]=[CH2:9]>>[CH3:1][Si:2]([CH2:9][CH2:8][CH2:7][CH:6]([CH3:10])[CH3:5])([Cl:4])[Cl:3]
Reactant: C[SiH](Cl)Cl
Reactant: C=CCC(C)C
Product: CC(C)CCC[Si](C)(Cl)Cl
Temperature: 50 °C

Procedure:
In a 25 ml apparatus, there were combined 2.6 g (0.023 mol) of MeSiHCl2, 2.0 g (0.023 mol) of EtMe2SiH, and 1.9 g (0.023 mol) of 4-methyl-1-pentene. A few droplets of Pt catalyst solution were added at 22° C. Gentle heating caused an exothermic reaction to 53° C. over 21 min., followed by heating at 50° C. for 130 min. VPC analysis of the complete reaction showed equivalent yields of MeSiCl2CH2CH2CH2CHMe2 and EtMe2SiCH2CH2CH2CHMe2. This example shows that while the promoting effect of EtMe2SiH is nearly equivalent to that of Et3SiH for the reaction of MeSiHCl2 with 4-methyl-1-pentene, its competitive reactivity is significantly higher.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:18][C:19]([CH3:21])=O.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:10][CH2:11][CH:12]([NH:15][CH:19]([CH3:21])[CH3:18])[CH2:13][CH2:14]3)[S:8][C:4]=2[CH:3]=1
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Reactant: CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylamine (335 mg), acetone (92 ul), acetic acid (0.1 mL) and methanol (3 mL) was stirred at room temperature for 5 minutes. To the reaction solution was added triacetoxy sodium boron hydride (332 mg). The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. Aqueous sodium hydrogencarbonate was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (160 mg). Yield: 41%.