Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][CH:13]([CH3:23])[CH2:14][CH2:15][NH:16][C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18].C(=O)(O)[O-].[K+]>CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([N:16]([CH2:15][CH2:14][CH:13]([CH3:23])[CH3:12])[C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)[C@H](C)NCCC(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)[C@H](C)N(CCC(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of 2,4-dichloro-5-nitropyrimidine (27.8 g, 144 mmol) in ether (350 mL) was cooled to −10° C. and was treated with methyl N-(3-methylbutyl)alaninate (20.8 g, 120 mmol). A solution of potassium bicarbonate (25.0 g in 180 mL water) was added drop wise maintaining the temperature below 0° C. Reaction mixture was then allowed to come to room temperature and stirred for 2 h. Ether layer was separated, the aq. layer was extracted with ether (3×100 mL). Combined ether solution was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate-hexane mixture (v:v=5:95) to give titled product (yield: 51%). 1HNMR (300 MHz, CDCl3): δ 0.90-1.01 (m, 6H), 1.40-1.61 (m, 6H), 3.10-3.21 (m, 1H), 3.39-3.45 (m, 1H), 3.78 (s, 3H), 4.41-4.50 (s, 1H), 8.71 (s, 1H).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[S:7]([CH:11]([NH2:15])[C:12]([OH:14])=[O:13])([OH:10])(=[O:9])=[O:8].CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C.C(OC(=O)C)C>[S:7]([CH:11]([N:15]1[CH:18]=[CH:22][CH:21]=[CH:20]1)[C:12]([OH:14])=[O:13])([OH:10])(=[O:9])=[O:8]
Reactant: NC(C(=O)O)S(=O)(=O)O
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)C(n1cccc1)S(=O)(=O)O

Procedure:
To a solution of sodium acetate (0.1 mole) in about 300 ml of glacial acetic acid is added about 0.05 mole of α-sulfo-α-aminoacetic acid hydrochloride. The solution is heated to reflux for 5 minutes, 2,5-dimethoxytetrahydrofuran (1 equivalent based on α-sulfo-α-aminoacetic acid hydrochloride) is added as quickly as possible, and the solution refluxed for an additional 2 minutes. The acetic acid is flash evaporated leaving a residue which is taken up in ethylacetate. The ethyl acetate is filtered, dried and evaporated to give α-sulfo-α-(1-pyrryl) acetic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[NH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[N:36]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4Cc4ccccc4)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 3.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9 and (R)-4-benzyloxazolidin-2-one (354 mg), the title compound (38 mg) was obtained.
Reaction SMILES: N1([C:7]2[C:8]([C:13]([NH:15][C@H:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[NH:21][C:22]3[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)=[O:14])=NC=CC=2)CCCCC1.Cl.FC(F)(F)C1N=CC(N[C@H]2CCC[C@@H]2N)=NC=1.[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=C(C=1)C(O)=O>>[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:8]([CH:7]=1)[C:13]([NH:15][C@H:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[NH:21][C:22]1[CH:27]=[N:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=1)=[O:14]
Reactant: O=C(O)c1cc(Cl)ccc1-n1nccn1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1N1CCCCC1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for 3-(piperidin-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide (Example 51) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 500 mg, 1.77 mmol) and 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; CAS number 1293284-54-4; 396 mg, 1.77 mmol) except this was purified only by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12]CC(O)=O>ClCCl>[CH3:7][O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:1][C:2]([Cl:4])=[O:3]
Reactant: COC(=O)CCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of oxalyl chloride (0.040 mole) in dichloromethane (20 mL) is added dropwise to an ice bath cooled solution of adipic acid monomethyl ester (Aldrich) (0.040 mole) in dichloromethane (50 mL). The reaction is stirred at ambient temperature for 5 hours. The reaction solution is washed with 5% aqueous sodium bicarbonate, with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give 6-methoxy-6-oxohexanoyl chloride. See Musso, et. al., J. Med. Chem., (2003) 46:409.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C:18]([NH:19][C:20](=[O:28])[CH2:21][CH2:22]1)=[CH:17][CH2:16]3)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.C(Cl)Cl>[C:29]([N:19]1[C:20](=[O:28])[CH2:21][CH2:22][C@@:23]2([CH3:24])[C:18]1=[CH:17][CH2:16][C@@H:15]1[C@@H:25]2[CH2:26][CH2:27][C@@:10]2([CH3:11])[C@H:12]1[CH2:13][CH2:14][C@@H:9]2[O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 17β-t-butyldimethylsilyloxy-4-azaandrost-5-en-3-one (2 g) in pyridine (5 ml) at 5°-10° C. was added benzoyl chloride (2 ml) in CH2Cl2 (10 ml) dropwise. After the addition, the mixture was stirred at 60° C. for 3 hours and poured onto ice-water. The mixture was extracted with methylene chloride, and dried (Na2 SO4). Removal of solvent gave the crude product which was recrystallized from CH2Cl2 -hexane to afford the title product.
Reaction SMILES: CC([S-])C.[Na+].[CH3:6][N:7]([CH3:39])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]3[O:22][C:23]4[C:28]([CH:29]([C:30]5([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31]5)[C:19]3=[CH:18][CH:17]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:12][CH:11]=1)=[O:9].Cl.C(OCC)(=O)C>CN(C=O)C>[CH3:6][N:7]([CH3:39])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]3[O:22][C:23]4[C:28]([CH:29]([C:30]5([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31]5)[C:19]3=[CH:18][CH:17]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:12][CH:11]=1)=[O:9]
Reactant: CCOC(=O)C1(C2c3ccccc3Oc3nc(-c4ccc(C(=O)N(C)C)cc4)ccc32)CCC1
Agent: CC(C)[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2ccccc2C3C2(C(=O)O)CCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
Sodium propane-2-thiolate (172 mg, 1.75 mmol) was added to a solution of the product from Step 2 (80 mg, 0.175 mmol) in DMF (5 mL) at room temperature. After 15 h at 60° C., the mixture was cooled to room temperature and adjusted pH2-3 with 1 N aqueous HCl. After addition of ethyl acetate (100 mL), the mixture was washed with water (10 mL), brine (10 mL), dried (MgSO4) and concentrated. Purification by preparative HPLC gave the desired 1-(2-(4-(dimethylcarbamoyl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)cyclobutanecarboxylic acid (45 mg, 60%). MS (ES+) m/z: 429 (M+H).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25]>C(#N)C>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCCBr
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN1CC=C(c2ccccc2)CC1

Procedure:
5 g of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (very toxic compound: New Engl. J. Med., 1983, 309, 310; Science, 1983, 219, 979; Psychiatry Res., 1979, 1, 249) and then 100 ml of acetonitrile are introduced into a 250 ml round-bottomed flask. 2.5 equivalents of anhydrous potassium carbonate are added and then 1.05 equivalents of 4-bromobutyronitrile, in solution in acetonitrile, are added dropwise. The mixture is heated at reflux for 16 hours and then filtered, the precipitate is washed with acetone and the filtrate is concentrated. The residue is taken up in ethyl acetate and washed 3 times with water. The organic phase is extracted with a 3M hydrochloric acid solution and the acid phase is washed with ethyl acetate. The acid phase is neutralized with 28% aqueous ammonia to pH>11. Extraction is carried out with ethyl acetate, the organic phase is washed with water and dried over anhydrous sodium sulphate and the mixture is concentrated. The nitrile is purified by chromatography on a silica column (eluent: ethyl acetate/hexane 80/20). White crystals are obtained. M.p.=57-59° C. Y=79%. 1H NMR (CDCl3, 330K): 1.81-1.95 (m, 2H, --CH2 --, 2.40-2.48 (t, 2H, --CH2 --), 2.54-2.60 (t, 4H, --H2C--CH2 --), 2.67-2.72 (t, 2H, --CH2 --), 3.12-3.17 (q, 2H, --CH2 --), 6.06-6.09 (m, 1H, --CH=), 7.24-7.44 (m, 5H, phe). 13C NMR (CDCl3): 14.7 (--CH2 --CH2 --C≡N), 22.8 (--CH2 --C≡N), 27.7 (>C--CH2 --CH2 --N<, pyrid), 50.0 (--CH2 --CH2 --N<, pyrid), 52.9 (=CH--CH2 --N<, pyrid), 55.9 (>N--CH2 --), 119.6 (--CN), 121.3 (>CH--), 124.6 (=CH--, pyri), 126.8 (>(CH)2 --), 128.1 (>CH)2 --), 134.7 (>C=C--, pyri), 140.4 (>C<).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3]C(C)(C)C)=O.[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=C=O)[CH:13]=1>C(#N)C>[CH3:21][C:12]1[CH:13]=[C:14]([NH:18][C:1]([NH:8][CH2:9][CH2:10][NH2:11])=[O:3])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1cccc(N=C=O)c1
Solvent: CC#N
Product: Cc1cccc(NC(=O)NCCN)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
N-Boc-Ethylene diamine (800 mg, 5 mmol) and m-tolyl isocyanate (665 mg, 5 mmol) were dissolved in acetonitrile and the mixture stirred at room temperature for 4 hrs. Solvent was removed under reduced pressure and the residue absorbed onto silica gel; prior to purification by flash column chromatography (silica, hexane:EtOAc 1:1) to yield the desired compound as a white solid (300 mg, 21%) (MS (+ESI, m/e) 294 (M+H)+). The N-Boc protected compound (300 mg, 1.02 mmol) was dissolved in formic acid (10 ml) and the mixture stirred at room temperature overnight. Excess acid was removed to yield the formate salt of the title compound as a white foam (210 mg).
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C@H:15]([C:23]2[CH:35]=[CH:34][C:26]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[C@@H:10]([CH3:36])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:38][C:39]([O:41]CC)=[O:40]>>[CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C@@H:15]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:38][C:39]([OH:41])=[O:40])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:34][CH:35]=2)[C@@H:10]([CH3:36])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccccc3)C[C@@H]2C)cc1
Reactant: CCOC(=O)CI
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OCC(=O)O)c2)N2C[C@@H](C)N(Cc3ccccc3)C[C@@H]2C)cc1
Yield: 84.6 %

Procedure:
Alkylation of 4-((alpha-R)-alpha-((2S,5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (Example 12) with ethyl iodoacetate, and subsequent hydrolysis of the ester as in Example 14 gave the title compound (84.6%) 1H NMR (0.1-M NaOD in CD3OD, 300 MHz); δ 1.10 (d, J=5.0 Hz, 3H); 1.11 (d, J=5.8 Hz, 3H; both doublets superimposed on m, 3H); 1.23 (m, 3H); 2.03 (m, 2H); 2.57 (m, 2H); 2.69 (m, 2H); 3.30 (m, 3H, superimposed on br m, 2H); 3.88 (d, J=13.1 Hz, 1H); 4.35 (s, 2H); 5.16 (s, 1H): 6.83 (m, 2H); 6.88 (s, 1H); 7.25 (m, 8H); 7.52 (d, J=8.1 Hz, 2H). Mass spectrum: (PFAB, glycerol matrix subtracted): m/z: 544.8, ((M+1)+, 82%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][O:27][NH:28][CH3:29]>C1COCC1>[CH3:26][O:27][N:28]([CH3:29])[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a stirred suspension of 1H-Indole-6-carboxylic acid (5.65 g, 35.1 mmol) in 55 mL of THF was added 1,1′-carbonyldiimidazole (6.25 g, 38.6 mmol). The suspension was stirred for 2 h at room temperature followed by addition of O,N-dimethyl-hydroxylamine hydrochloric acid (4.10 g, 42.1 mmol) in an ice-bath. The mixture ws stirred at room temperature overnight. The mixture was extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed brine (50 mL), dried over MgSO4, filtered and concentrated to an oil, which was purified by flash column chromatography (EtOAc/Hexane) to give 1H-Indole-6-carboxylic acid methoxy-methyl-amide as an oil (5.54 g, 77% yield): 1H NMR (CDCl3) δ 3.39 (s 3H, NCH3), 3.58 (s, 3H, OCH3), 6.55-6.57 (m, 1H, Ar), 7.29-7.84 (m, 4H, Ar), 8.85 (brs, 1H, NH). The product was used in the next step without further purification.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([O-:10])=[N:9][C:4]2=[CH:3][CH:2]=1.[Na+]>C(O)(=O)C.O>[N:1]1[N:5]2[CH:4]=[N:9][C:8](=[O:10])[CH2:7][C:6]2=[CH:3][CH:2]=1
Reactant: [O-]c1ccn2nccc2n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2ccnn2C=N1
Yield: 85.5 %

Procedure:
Sodium pyrazolo[1,5-a]pyrimidin-5-olate (13.47 g) was dissolved in 500 mL of acetic acid and 100 mL of water, stirred 15 minutes then evaporated to dryness under vacuum. The residue was suspended in 300 mL of 9:1 dichloromethane:methanol and vacuum filtered through silica gel to remove sodium acetate. The silica gel pad was washed with 700 mL of additional dichloromethane:methanol solution. The combined dichloromethane:methanol solution was concentrated to dryness. The solid product was suspended in 1:1 hexane:dichloromethane and filtered to yield 9.9 g (85%) pyrazolo[1,5-c]pyrimidin-5(4H)-one. LCMS (ESI) m+H=136.0; 1H NMR (400 MHz, DMSO-d6) δ: 12.1 (s broad exchangeable, 1H), 8.47 (d, 1H, J=7.9), 7.75 (d, 1H, J=1.9), 5.94 (d, 1H, J=7.5), 5.81 (d, 1H, J=1.7).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:10]([CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[C:9]([N:8]=[C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]2)[CH:21]=1
Reactant: O=C1CCCCN1
Reactant: Nc1cc(Cl)ccc1CN1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Clc1ccc(CN2CCOCC2)c(N=C2CCCCN2)c1

Procedure:
A mixture of 2-piperidone (6 g) in benzene (50 ml), 4-(2-amino-4-chlorobenzyl)morpholine (6.8 g) in benzene (50 ml) and phosphorus oxychloride (5.5 ml) was heated at 60°-65° C. for 5 hours to give 4-[4-chloro-2-(2-piperidinylideneamino)benzyl]morpholine (m.p. 121°-122° C.) which was recrystallised from hexane.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[C:3]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[C:3]=1[CH:24]([CH2:40][CH2:39][CH3:43])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc2c(c1)OCO2)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc2c(c1)OCO2)CCCC3
Yield: 82.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.328 g; 0.83 mmol), LHMDS 1N in THF (1.24 mL; 1.24 mmol), 1-iodopropane (0.162 mL; 1.66 mmol) in DMF (4.1 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-40%) in heptane furnished 0.300 g (83%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([CH2:17][CH2:18][N:13]3[C@@H:12]3[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][C@H:11]23)[CH:16]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([CH2:17][CH2:18][N:13]3[C@@H:12]3[CH2:19][CH2:20][NH:21][CH2:22][C@H:11]23)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccccc3Cl)cc3c1N2CC3
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccccc1-c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Tert-butyl (±)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (45.1 mg, 0.11 mmol) was dissolved in 20% TFA in methylene chloride (4 mL) and was stirred at RT for 2 h. The reaction was solution was cooled to 0° C. and basified with 1M NaOH until pH>14. The layers were separated. The aqueous phase was extracted the methylene chloride (2×10 ml). The organic layers were washed with brine and dried. Concentration afforded the title compound (29.3 mg, 86%) as a pale yellow amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.42 (dd, 1H, J=1.4, 7.3 Hz), 7.16-7.33 (m, 3H), 7.02 (s, 1H), 6.96 (s, 1H), 3.69 (dt, 1H, J=1.4, 8.1 Hz), 3.15-3.50 (m, 5H), 3.06 (dt, 1H, J=3.2, 12.3 Hz), 2.82-2.97 (m, 3H), 1.78-1.93 (m, 2H) ppm. MS (CI, NH3): 311 (base, M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Product: CC(=O)Nc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(acetylamino)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.16 min; Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([O-])(O)=O.[Na+].[C:19](=[O:26])([O:23][CH2:24]I)[S:20][CH2:21][CH3:22]>O.C(Cl)Cl>[C:19](=[O:26])([O:23][CH2:24][O:12][C:11](=[O:13])[CH2:10][CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[S:20][CH2:21][CH3:22]
Reactant: CCSC(=O)OCI
Reactant: CCOP(=O)(CCC(=O)O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(CCC(=O)OCOC(=O)SCC)OCC
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
To a mixture of 3-(diethylphosphono)propanoic acid (79, 1.0 g, 4.76 mmol) in H2O (12 mL) and CH2Cl2 (12 mL) was added NaHCO3 (1.0 g, 11.9 mmol) and TBAHSO4 (1.62 g, 4.76 mmol). After stirring for 20 min, S-ethyl O-iodomethyl carbonothioate (1.17 g, 4.76 mmol) in CH2Cl2 (2 mL) was added. The biphasic reaction was stirred vigorously for 4 h 20 min and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on a Biotage™ flash chromatography system, using EtOAc as the eluent, to yield compound 80 (1.29 g, 83%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.30-1.65 (m, 9H), 2.03-2.12 (m, 2H), 2.64-2.71 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 4.06-4.14 (m, 4H), 5.82 (s, 2H). 31P NMR (162 MHz, CDCl3) δ 30.45 (s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:32]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:32][C:28]4[S:27][CH:31]=[CH:30][N:29]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1nccs1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3nccs3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 2-thiazolecarboxaldehyde to provide 28 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([C:5]3[S:6][C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)=[CH:3][CH:4]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Br)s2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(-c3cnc(N)nc3)s2)n1

Procedure:
The title compound was prepared from 2-(5-bromo-thiophen-2-yl)-4-(3,4-dichlorophenyl)-6-methyl-pyridine (example E.87) (0.25 g, 0.626 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.152 g, 0.689 mmol) according to the general procedure VI. Obtained as a yellow solid (0.060 g, 23%). MS (ISP) 413.1 [(M+H)+], 415.2 [(M+2+H)+] and 417 [(M+4+H)+]; mp 237° C.