Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3].[N:25]1([C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:28]2[CH2:29][CH2:30][N:25]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:26][CH2:27]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: CCCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(propyl)-amide and 2-(piperazin-1-yl)-quinoline.
Reaction SMILES: Br[C:2]1[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:5]3[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=3[CH:3]=2)=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1F
Reactant: CSc1ncc2cc(Br)c(=O)n(C(C)C)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1ncc2cc(-c3ccc(F)c([N+](=O)[O-])c3)c(=O)n(C(C)C)c2n1
Temperature: 80 °C
Yield: 109.5 %

Procedure:
To a degassed solution of 6-bromo-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)one (0.78 g, 2 mmol; J. Med. Chem., 48, 2371, 2005) in DME (10 ml) was added Pd(PPh3)4 (0.1 g, 5% mol), 4-fluoro-3-nitrophenylboronic acid (0.5 g, 3 mmol) and 2M Na2CO3 solution (3 ml, 6 mmol) and the mixture was heated to 80° C. for 16 h. The mixture was poured into water (40 mL), and product was extracted with EtOAc (3×25 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo afforded crude product. Purification by silica gel chromatography provided 6-(4-fluoro-3-nitrophenyl)-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as off-white solid (0.82 g, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.52 (dd, J=7.2 Hz, 2.4 Hz, 1H), 8.28 (s, 1H), 8.15-8.12 (m, 1H), 7.70 (dd, J=11.6 Hz, 8.8 Hz, 1H), 5.81-5.78 (m, 1H), 2.63 (s, 3H), 1.60 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 375.0 (M+H+).
Reaction SMILES: OC[CH2:3][C:4]1[C:9](=O)[N:8]2[N:11]=[CH:12][CH:13]=[C:7]2[NH:6][C:5]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].P(Cl)(Cl)([Cl:21])=O.C(N(CC)CC)C.[CH:31]([Cl:34])(Cl)Cl>>[Cl:21][C:9]1[N:8]2[N:11]=[CH:12][CH:13]=[C:7]2[N:6]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1[CH2:3][CH2:31][Cl:34]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)c1[nH]c2ccnn2c(=O)c1CCO
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2ccnn2c(Cl)c1CCCl
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 58.5 %

Procedure:
To 5.36 g (21.35 mmol) of ethyl 6-(2-hydroxyethyl)-pyrazolo-[1,5-a]pyrimidin-7(4H)-one-5-carboxylate were added 7 ml (d=1.645, 75.10 mmol) of phosphorus oxychloride, and the mixture was stirred for 40 minutes in an oil bath heated to 100° C. under a nitrogen atmosphere. The reaction mixture was then cooled to about room temperature, and 7 ml (d=0.726, 50.32 mmol) of triethylamine were added to the mixture. The resultant mixture was stirred for 30 minutes in the oil bath heated to 100° C. Thereafter, the reaction mixture was cooled with ice water, and 100 ml of chloroform were added thereto. The resultant mixture was poured into 600 ml of ice water. The chloroform layer was separated, and the water layer was extracted with chloroform (100 ml×2). After all the chloroform layers were put together and dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to column chromatography on silica gel (chloroform) to obtain 3.60 g (yield: 58.5%) of the intended product.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C(OCC)C>[OH:3][CH2:4][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1
Reactant: CCOC(=O)CC1CN(Cc2ccccc2)CCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: OCCC1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution of 2-ethoxycarbonylmethyl-4-benzylmorpholine (41 g) in diethyl ether (100 ml) is added dropwise to a stirred suspension of lithium aluminum hydride (59.2 g) in diethyl ether (150 ml). The reaction mixture is stirred at 25° C. for 1 hour. The excess of lithium aluminum hydride is decomposed by the successive addition of ethyl acetate and water. The insoluble materials are filtered off, and the filtrate is evaporated to give the title compound (34.4 g) as an oil. The starting material, 2-ethoxycarbonylmethyl-4-benzylmorpholine, is prepared according to the method of F. Loftus [Syn. Commun., 10, 59-73 (1980)].
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:21][NH:22][CH3:23].[CH2:24]=O>C(O)(=O)C>[CH3:21][N:22]([CH2:24][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH3:23]
Reactant: CNC
Reactant: C=O
Reactant: CCCCCCCCCC(=O)N1CCc2ccoc2C1
Solvent: CC(=O)O
Product: CCCCCCCCCC(=O)N1CCc2cc(CN(C)C)oc2C1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.230 g (0.829 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)decan-1-one in 20 ml of acetic acid, 0.090 ml (1.0 mmol) of 50% aqueous dimethylamine and 0.080 ml (1.0 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=9/1) to yield the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:9]=2[CH:23]=1)=O.C[O-].[Na+].O.C([NH2:30])=O>>[CH2:16]([NH:15][CH:11]1[CH2:10][C:9]2[CH:23]=[C:5]([C:3]([NH2:30])=[O:2])[CH:6]=[CH:7][C:8]=2[CH2:14][CH2:13][CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: 110 °C

Procedure:
A mixture of 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (4.21 g) and sodium methoxide (2.21 g) in formamide (42 ml) was heated at 110° C. for 2 hours. After cooling, the reaction mixture was poured into water, and the product was extracted with ethyl acetate. The organic layer was washed with water (twice) and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1 to 10:1) to afford 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxamide (2.71 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CO>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:18][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: OCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: N#Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Temperature: 120 °C
Yield: 80.2 %

Procedure:
A mixture of 2-fluoro-5-nitro-benzonitrile (290 m g, 1.74 mmol), 3-flouro-benzyl alcohol (1220 mg, 1.74 mmol) and K2CO3 (219 mg, 2.09 mmol) in DMA (4 ml) was heated at 120° C. for 7 h. The mixture was cooled to rt, diluted with MeOH(10 ml), filtered and purified by preparative HPLC to give 20A (380 mg, 80%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1.OO.[OH2:23].C(O)(=[O:26])C>>[CH3:1][S:2]([C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1)(=[O:26])=[O:23]
Reactant: O
Reactant: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Reactant: CC(=O)O
Agent: OO
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 75 °C
Yield: 98.2 %

Procedure:
To a slurry of 10.0 g (0.0350 moles) of 2-(4-(methylthio)phenoxy)-5-nitrobenzonitrile in 75 ml of glacial acetic acid heated at 60° C. was added 15.85 g of aqueous 30% hydrogen peroxide (0.140 moles) over 5 minutes. An additional 25 ml of glacial acetic acid was added and the mixture heated at 75° C. for 3 hrs. The reaction mixture was cooled and poured into water. The product was collected by filtration, washed with water and dried to obtain 10.9 g of product (98.2% yield), mp 205°-206.5° C. Recrystallization from methanol gave purified 2-(4-(methylsulfonyl)phenoxy)-5-nitrobenzonitrile, mp 206°-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([O:43][C:44]([F:47])([F:46])[F:45])[CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:39]([C:36]1[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][C:35]=1[O:43][C:44]([F:45])([F:46])[F:47])(=[O:41])=[O:40])[C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([N:28]([CH3:29])[CH3:30])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccccc1C1(N2CCCC[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3CCCC[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 40.4 %

Procedure:
With 500 mg of (2S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide, which is the compound described in Preparation 3.49 (Isomer B) of Publication No. WO01/98295 and 374 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 322 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN([CH2:41][C:42]3C=CC=[CH:44][C:43]=3Cl)C=2N=1)(C)(C)C.C1(N)CCCCC1>>[C:1]([C:5]1[N:6]=[C:7]([NH:22][CH:27]2[CH2:26][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: NC1CCCCC1
Product: CC(C)(C)c1nc(NC2CCCCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and cyclohexane-amine and isolated as light-yellow solid (3.8 mg, 20%). MS (m/e): 399.4 (MH+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:24]([O:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33][NH2:34])[CH3:31])([CH3:27])([CH3:26])[CH3:25].O>CN1CCCC1=O>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:34][CH2:33][CH2:32][N:30]([CH3:31])[C:29](=[O:35])[O:28][C:24]([CH3:25])([CH3:26])[CH3:27])[S:3][C:4]=3[CH:10]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(NC(=O)c2ccc3nc(Br)sc3c2)cc1OC
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(NC(=O)c2ccc3nc(NCCN(C)C(=O)OC(C)(C)C)sc3c2)cc1OC
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 2-bromo-N-(3,4-dimethoxyphenyl)benzo[d]thiazole-6-carboxamide (392.4 mg, 0.998 mmol), N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (193.4 mg, 1.11 mmol) and N—N-diisopropylethylamine (148.6 mg, 1.15 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was stirred in a preheated oil bath at 120° C. for 4 h, then allowed to cool to room temperature, poured into water and extracted into ethyl acetate. The organic layer was washed with water, dried (sodium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by gradient flash column chromatography, eluting with 70% to 80% ethyl acetate in heptane to yield tert-butyl 2-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-ylamino)ethyl(methyl)carbamate as a beige powder.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:14]([CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:49][O:50][CH2:51][CH2:52]O.C(Cl)Cl.CCOC(/N=N/C(OCC)=O)=O>>[F:1][C:2]1[C:3]2[N:4]([C:14]([CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH2:52][CH2:51][O:50][CH3:49])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2cc(F)c3nnc(COc4ccnc5cc(O)ccc45)n3c2)on1
Reactant: COCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOc1ccc2c(OCc3nnc4c(F)cc(-c5cc(C)no5)cn34)ccnc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol (0.110 g, 0.28 mmol), PPh3 (polymer supported: 2.3 mmol/g) (1.2 g, 2.8 mmol) and 2-methoxyethanol (0.11 ml, 1.3 mmol) were combined in DCM (11 ml, 0.28 mmol). The mixture was cooled to 0° C., and DEAD (0.089 ml, 0.56 mmol) was added dropwise. The reaction was removed from the ice bath, and stirred at RT for 1 h. The material was diluted with DCM, and the PS—PPh3 was filtered off and washed thoroughly with DCM. The filtrate was concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting with 0-100% 90:10:1 DCM:MeOH:NH4OH in DCM) to yield 4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-(2-methoxyethoxy)quinoline (0.070 g, 55% yield) as a white solid. MS (ESI pos. ion) m/z: 450.0 (M+H). Calc'd Exact Mass for C23H20FN5O4: 449.44
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[Cl:31])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26](/[CH:27]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:25][C:24]=1[Cl:31])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)c(Cl)c2)c(O)c([N+](=O)[O-])c1
Yield: 59.6 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (750 mg, 3.84 mmol) and 4-benzyloxy-3-chlorobenzaldehyde (1 g, 3.84 mmol) were reacted according to the same procedure as Preparation 15 to give 970 mg (Yield 59%) of the title compound.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]#[C:25][C:26]([OH:28])=O)[CH2:19][CH2:18]1.[Br:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([NH2:47])[CH:45]=3)[N:40]=[CH:39][N:38]=2)[CH:33]=[CH:34][CH:35]=1>N1C=CC=CC=1.O1CCCC1>[Br:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([NH:47][C:26](=[O:28])[C:25]#[C:24][CH2:23][N:20]4[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]4)[CH:45]=3)[N:40]=[CH:39][N:38]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CN1CCN(CC#CC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN1CCN(CC#CC(=O)Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
Isobutyl chloroformate (0.905 g, 6.6 mmol) and N-methylmorpholine (1.550 g, 15.3 mmol) were added to an ice cold solution of 1.900 g (10.71 mmol) of 4-(4-methyl-piperazin-1-yl)-but-2-ynoic acid in l50 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 12 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, then it was poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (30:70), gave 0.590 g of 4-(4-methyl-piperazin-1-yl) -but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 479.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][C:20](Cl)=[C:19](Cl)[CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.N1CCCC[CH2:42]1.C(N1CC[C@H]([C@H]([OH:62])C)[C@@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.CC1C=CC(O)=CC=1.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([OH:26])=[O:62])[CH2:28][CH2:29]2)=[N:34][CH:35]=1)#[N:40].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:42])=[CH:21][CH:22]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C1CCNCC1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: Cc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc(O[C@@H](C)[C@H]2CCN(C(=O)C3CCN(c4ccc(C#N)cn4)CC3)C[C@@H]2c2ccc(Cl)cc2)cc1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 4-methyl-phenol via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as viscous yellow oil. MS (m/e): 543.5 [(M+H)+].
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:26]I.O>CS(C)=O>[Cl:3][C:4]1[C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][C:20]([O:23][CH3:26])([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Cl)c2C1=O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(C)(C)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 0.75 h

Procedure:
1.20 g (18.6 mmol) of freshly powdered potassium hydroxide was stirred at room temperature for 5 minutes in 15 ml of dimethyl sulfoxide. 1.65 g (5 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 1.42 g (10 mmol) of methyl iodide were then added thereto in succession, whereby the temperature rises to 35°. The reaction mixture was stirred for 45 minutes and then poured into 50 ml of water. The mixture was extracted five times with methylene chloride, the combined organic phases were dried over magnesium sulphate and evaporated. After crystallization from diisopropyl ether there was obtained 7-chloro-4,5-dihydro-3-(3-methoxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 172°-174°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8](Cl)(Cl)=[O:9])[CH3:2].[CH2:23]([NH:26][CH2:27][CH:28]=[CH2:29])[CH:24]=[CH2:25]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8]([N:26]([CH2:27][CH:28]=[CH2:29])[CH2:23][CH:24]=[CH2:25])([N:26]([CH2:27][CH:28]=[CH2:29])[CH2:23][CH:24]=[CH2:25])=[O:9])[CH3:2]
Reactant: CCOC(=O)CN(CP(=O)(Cl)Cl)C(=O)SCc1ccccc1
Reactant: C=CCNCC=C
Solvent: CCOCC
Product: C=CCN(CC=C)P(=O)(CN(CC(=O)OCC)C(=O)SCc1ccccc1)N(CC=C)CC=C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Freshly prepared ethyl-N-[(benzylthio)carbonyl]-N-[dichlorophosphinylmethyl]-glycinate (12 g.; 0.031 mol.) dissolved in 150 ml. of diethyl ether was added to a solution containing diallylamine (12.15 g.; 0.125 mol.) in 150 ml. of diethyl ether. The reaction mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with 3% ammonium hydroxide, 5% hydrochloric acid and then water. The ether layer was separated, then dried and concentrated in vacuo to yield ethyl-N-[(benzylthio)carbonyl]-N-[bis(diallylamino)phosphinylmethyl]-glycinate, hemi-hydrate (10.1 g.) as an oil (nD25 =1.5373) having the following analysis:
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH:5]=O)=[CH2:4].Cl[CH:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].S(=O)(=O)([O-])[NH2:22].[NH4+]>C(O)C>[CH2:2]([C:3]1[CH:4]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:22][CH:5]=1)[CH3:1]
Reactant: CCOC(=O)C(=O)C(Cl)C(=O)OCC
Reactant: NS(=O)(=O)[O-]
Reactant: C=C(C=O)CC
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Temperature: 25 °C
Yield: 86 %

Procedure:
A stirred mixture of ethacrolein, (4.2 g, 0.05 mol), diethyl 3-chloro-2-oxo-butanedioate, (11.2 g, 0.05 mol) and ammonium sulfamate, (15.4 g, 0.135 mol) in ethanol (37 mL) is heated at reflux. After 15 hours the mixture is cooled to room temperature and the solvent removed by distillation under reduced pressure. The residue is treated with water and extracted with ethyl acetate. The organic phase is separated and concentrated in vacuo and the residue purified by column chromatography on silica gel using 4:1 hexane-ethyl acetate as the eluent to give 10.8 g (75% yield) of the title product as an oil which is shown to be 95% pure by a gas chromatography assay.