Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32]C1C=CC(C#N)=C(O)C=1.C(O)(=O)C(O)=O.[Cl:48][C:49]1[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[C:51]([O:57][C@@H:58]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:59][CH2:60][CH2:61]NC)[CH:50]=1>O1CCCC1.C1(C)C=CC=CC=1>[Cl:48][C:49]1[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[C:51]([O:57][C@@H:58]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:59][CH2:60][CH2:61][Cl:32])[CH:50]=1
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: CNCCC[C@@H](Oc1cc(Cl)ccc1C#N)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Cl)cc1O[C@H](CCCCl)c1ccccc1
Yield: 197.8 %

Procedure:
Diethyl azodicarboxylate (1.86 g) was added dropwise to a solution of triphenylphosphine (2.81 g), 4-chloro-2-hydroxybenzonitrile (1.49 g) and the product from step (a) (1.79 g) in tetrahydrofuran (5 ml) and toluene (60 ml) at 0° C. and stirred at 0° C. for 4hand at 20° C. for 18 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica eluting with hexane-diethyl ether (4:1) to give the title compound as a colourless oil (2.80 g).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C:5]1=O)([CH3:3])[CH3:2].[CH2:12]1CC2C(CC(CC2)=O)CC1>>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C:5]1=[CH2:12])([CH3:3])[CH3:2]
Reactant: O=C1CCC2CCCCC2C1
Reactant: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Product: C=C1C[C@H](C)CC[C@H]1C(C)C

Procedure:
The title compound was prepared as described in Example 45A substituting (2S,5R)-2-isopropyl-5-methylcyclohexanone, purchased from Aldrich, for 2-decalone.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1([C:18]([OH:20])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[NH2:22][CH:23]([CH2:29][SH:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>CN(C=O)C>[CH:13]1([C:18]([NH:22][CH:23]([CH2:29][SH:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)C(N)CS
Reactant: O=C(O)C1CCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(CS)NC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
CDI (8.5 g) was added to a solution of cyclopentanecarboxylic acid (5.2 mL) in DMF (40 mL). The resulting mixture was stirred for 1 h and cooled in an ice bath. Ethyl 2-amino-3-mercaptopropanoate hydrochloride (8.88 g) was added, followed by triethylamine (10 mL). The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing the product were combined and evaporated to give the subtitled compound as a white solid. Yield 7.7 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C=CC(C2C=NN(C[C@H]3COC(C)(C)O3)C=2)=C2C=1C(=[O:60])N(C)C2>>[CH2:40]([O:39][P:38]([CH2:37][C:36]1[CH:46]=[CH:47][C:33]([NH:32][C:24]2[N:23]=[C:22]([NH:21][C:13]3[CH:12]=[CH:11][C:10]([C:8]4[CH:7]=[N:6][N:5]([CH2:4][C@H:3]([OH:60])[CH2:2][OH:1])[CH:9]=4)=[C:18]4[C:14]=3[C:15](=[O:20])[N:16]([CH3:19])[CH2:17]4)[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=2)=[C:34]([O:48][CH3:49])[CH:35]=1)(=[O:45])[O:42][CH2:43][CH3:44])[CH3:41]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(-c3cnn(C[C@H]4COC(C)(C)O4)c3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C[C@H](O)CO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Yield: 48 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 7-amino-4-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-4-yl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 5C, 337 mg, 742 μmol) to afford 254 mg of the desired product (48%). 1H NMR (400 MHz, CD3OD) δ 8.49 (br. s., 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.67-7.77 (m, 2H), 7.11 (s, 1H), 7.00 (d, J=8.1 Hz, 1H), 4.61 (s, 2H), 4.37 (dd, J=4.3, 13.9 Hz, 1H), 4.15-4.24 (m, 1H), 4.00-4.14 (m, 5H), 3.90 (s, 3H), 3.52-3.56 (m, 2H), 3.35 (d, J=7.1 Hz, 2H), 3.21 (s, 3H), 1.26 (dt, J=2.7, 7 Hz, 6H). MS (ESI): m/z 720.23 [M+H]+. UPLC: tR=1.12 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].N1C=CC=CC=1.Cl.[CH3:18][NH:19][O:20][CH3:21]>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7]([N:19]([O:20][CH3:21])[CH3:18])=[O:8]
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc(Cl)sc1Cl
Reaction time: 18 h
Yield: 90.8 %

Procedure:
To a stirred solution of 2,5-dichloro-3-thiophenecarbonylchloride (1.08 g, 5.0 mmol) and pyridine (2 mL) in CH2Cl2 (10 mL) was added N,O-dimethylhydroxylamine hydrochloride (490 mg, 5.0 mmol) at room temperature, and the mixture was stirred for 18 hours. CH2Cl2 (10 mL) was added to the mixture. The combined organic layers were washed with 1N HCl solution, saturated NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo to give light yellow oil (1.09 g, 91% yield). The compound was used for next reaction without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[C:14]2[N:15]=[C:16]([O:32][CH2:33][CH3:34])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=3)[C:18](=[O:19])[C:13]=2[CH:12]=[CH:11][N:10]=1.O>CN(C)C=O>[CH2:33]([O:32][C:16]1[N:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=2)[C:18](=[O:19])[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:14]=2[N:15]=1)[CH3:34]
Reactant: COCCO
Reactant: CCOc1nc2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2c(OCCOC)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxyethanol (0.019 ml) in N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 9 mg) at room temperature, and the mixture was stirred for 30 min. 8-Chloro-2-ethoxy-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[3,4-d]pyrimidin-4(3H)-one (80 mg) was added to reaction mixture, and the mixture was stirred at 60° C., for 5 hr, and allowed to be cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was suspended in a mixed solvent of ethyl acetate/hexane, and the resulting solid was collected by filtration to give the title compound (21 mg).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH:1]1([CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]([N:20]3[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]3)=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (28% yield). 1H NMR (400 MHz, CDCl3) δ 8.04, 7.89, 7.73, 7.65, 7.58, 7.38, 6.99, 4.08-3.67, 3.54-3.46, 3.39-3.31, 1.77-1.66, 1.34-1.23, 0.72-0.62, 0.45-0.36, 0.06-0.04. MS (ES+) m/z 462.2 (M+1).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:13][CH:14]=1)(C(C)(C)C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][CH2:28][O:29][CH3:30]>CC#N>[CH3:30][O:29][CH2:28][CH2:27][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:13][CH:14]=1
Reactant: COCCBr
Reactant: COC(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCOc1ccc(CC(=O)OC)nc1

Procedure:
To a stirred solution of methyl 2-(5-((tert-butyldimethylsilyl)oxy)pyridin-2-yl)acetate (500 mg, 3 mmol) in MeCN was added Cs2CO3 (1.4 g, 4.5 mmol) followed by 1-bromo-2-methoxyethane (621 mg, 4.5 mmol) at room temperature. The whole mixture was heated to 80° overnight. LC-MS showed desired product. It was filtered, evaporated and purified by a standard method.
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:2].O[N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]([O:14][N:34]2[C:38](=[O:39])[CH2:37][CH2:36][C:35]2=[O:40])=[O:13])[CH2:8][CH2:7]1)#[N:2]
Reactant: N#CC(CCN1CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: N#CC(CCN1CCC(C(=O)ON2C(=O)CCC2=O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
24.5 Grams of 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid are dissolved in 225 ml. of redistilled N,N-dimethylformamide by warming to about 60°C. To the warm solution were added, with stirring, 9.0 grams of recrystallized N-hydroxysuccinimide, followed by 12.4 grams of dicyclohexylcarbodiimide. A precipitate appears upon cooling to room temperature. The suspension is stirred at room temperature under anhydrous conditions for about 36 hours, then is cooled to approximately 5°C. and is filtered to remove the precipitate. The filtrate is diluted with approximately 400 ml. of ethyl acetate and 200 ml. of water. The organic layer is then separated and washed three times with water, solid sodium chloride being added as needed to break the emulsion formed. The solution is dried over anhydrous sodium sulfate and partially concentrated until a precipitate forms. Filtration and recrystallization of the precipitate from a mixture of tetrahydrofuran and isopropyl ether affords N-[1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carbonyloxy]succinimide, melting at about 156.5°-157.5°C. This product has the formula ##SPC3##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:2]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:2]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1cncc(CN2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCN(Cc3cccnc3)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A suspension of 1-(pyridin-3-ylmethyl)piperazine (549 mg, 3.10 mmol), 4-fluorobenzonitrile (375 mg, 3.10 mmol), and K2CO3 (643 mg, 4.65 mmol) in DMF (50 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and filtered, and the filtrate was washed with ethyl acetate (30 nL). The combined filtrate and washings were evaporated to dryness under reduced pressure. The crude residue was purified by MPLC on silica gel (3% MeOH in CH2Cl2) to afford the titled compound (326 mg, 38%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25])[C:6]1=[O:39])[CH2:2][CH2:3][CH3:4].[NH:40]1[CH:44]=[CH:43][CH:42]=[N:41]1>>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33][C:44]3[CH:43]=[CH:42][NH:41][N:40]=3)[CH:30]=[CH:29][C:28]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25])[C:6]1=[O:39])[CH2:2][CH2:3][CH3:4]
Reactant: c1cn[nH]c1
Reactant: CCCCn1c(=O)c(NC(=O)Nc2cc(CBr)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Product: CCCCn1c(=O)c(NC(=O)Nc2cc(Cc3cc[nH]n3)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21

Procedure:
In the same manner as in Example 8 (b), the title compound is prepared from N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2-tert-butyl-5-(bromomethyl)phenyl]urea and pyrazole.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.[CH:21]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28]>>[C:22]1([CH3:28])[CH:23]=[CH:24][CH:25]=[C:26]([O:27][C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:20])=[O:19])=[CH:13][CH:14]=2)[CH:21]=1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(I)cc1
Reactant: Cc1cccc(O)c1
Product: Cc1cccc(Oc2ccc(C(=O)Nc3ccccc3C(=O)O)cc2)c1

Procedure:
In analogy to example 2,2-(4-m-Tolyloxy-benzoylamino)-benzoic acid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3] and m-cresol. MS (m/e): 346.3 (M−H−, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.Cl[C:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([CH3:27])[CH:9]=1>>[CH3:27][C:10]1[CH:9]=[C:8]([O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Reactant: OC1CCOC1
Product: Cc1cc(C)c(-c2cccc3c(OC4CCOC4)cc(C)nc23)c(C)c1

Procedure:
The title compound was prepared as a light yellow solid starting from 3-hydroxytetrahydrofuran and 4-chloro-2-methyl-8-(2,4,6-trimethyl-phenyl)-quinoline using procedure analogous to that described in Example 5. 1H NMR (CDCl3) δ 8.17(d,1H), 7.39-7.46(m,2H), 6.96(s,2H), 6.49(s,1H), 5.13(m,1H), 4.14(d,2H), 3.8-4.1(m,4H), 2.51(s,3H), 2.36(s,3H), 2.15-2.20(m,2H), 1.89(s,6H)ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=[CH:20][C:19](=[O:21])[CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: CC(=O)C=CC=Cc1ccc(OCc2ccccc2)cc1
Yield: 79.5 %

Procedure:
A solution of 19.7 g of p-benzyloxycinnamaldehyde and 27.6 g of acetylmethylenetriphenylphosphorane in 190 ml of xylene was heated under reflux for 2 hours, the solvent was then evaporated and the residual crystals were recrystallized from benzene to give 18.3 g of the desired compound melting at 132°-133° C.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[CH3:20][C:21]1[C:29]2[C:28]([N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:27][CH:26]=[N:25][C:24]=2[S:23][CH:22]=1>>[OH:16][CH:15]([CH2:17][NH:36][CH:33]1[CH2:32][CH2:31][N:30]([C:28]2[C:29]3[C:21]([CH3:20])=[CH:22][S:23][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:35][CH2:34]1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=1
Reactant: Cc1csc2ncnc(N3CCC(N)CC3)c12
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Product: Cc1csc2ncnc(N3CCC(NCC(O)COc4ccc(O)cc4)CC3)c12
Yield: 11 %

Procedure:
Synthesis followed SP6 (3 h), using 150 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) with 11% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 76% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([O:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
95 mg (0.35 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.10 g (0.34 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.86 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down, the precipitate was suction filtered and dried i. vac.
Reaction SMILES: [CH:1]1([CH2:11]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[OH-].[Na+]>>[CH:1]1([CH2:11][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: ClCC1OCCc2ccccc21
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(c1)CCOC2CN1CCNCC1
Yield: 70.7 %

Procedure:
To 1 g (5.48 mmol) of (isochroman-1-yl)methyl chloride obtainable by Reference Example 1 was added 2 g (23.3 mmol) of piperazine, and the resulting mixture was heated at 100° to 120° C. for 10 hours. After being cooled, the mixture was basified with the addition of 10% sodium hydroxide and then extracted with chloroform. The extract was washed with water and then dried. The solvent was evaporated off. The residue was distilled under reduced pressure (150° C./15 mmHg) to give 0.9 g (74%) of the desired compound as an oily.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:17][CH2:18][C:19]#[N:20])[CH2:6][CH2:7][N:8]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:10][C:11]#[N:12])#[N:2].[H][H]>CO.N.[Ni]>[NH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:7][CH2:6][N:5]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: N#CCCN(CCC#N)CCN(CCC#N)CCC#N
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCN(CCCN)CCN(CCCN)CCCN

Procedure:
Preparation of CH3 (CH2)6C(O)N CH2 (CHOH)4CH2OH!--(CH2)3 !2--N(CH2)2N-- (CH2)3 -- CH2 (CHOH)4CH2OH!NC(O)(CH2 6CH3 !2One mole of ethylenediamine (60g) is added to 250 g (4.7 moles) acrylonitrile and heated to 100° C. for 2 hrs. Excess acrylonitrile is vacuum stripped to give about 200 g tetrakis (2-cyanoethyl)ethylenediamine. The nitrile is dissolved in 2 l dry methanol saturated with ammonia. It is hydrogenated in the presence of 20 Raney nickel at 100°-120° C. for 3 hrs under 1000-1500 psi hydrogen. The sample is decanted, filtered and stripped under vacuum to give about 200 g tetrakis(3-aminopropyl)ethylenediamine. The whole sample (200 g, 0.7 mole) is added to 5040g 10% aqueous glucose (2.8 mole) and reduced with hydrogen at 1500 psi in the presence of 50 g Raney nickel. The sample is decanted, filtered and stripped to give about 600 g (0.63 mole) tetrakis(glucitylaminopropyl)ethylenediamine. The latter is stripped dry and melted in 200 g propylene glycol. Methyl octanoate (398 g, 2.5 mole) is added along with 0.1 mole 25% sodium methoxide/methanol. The sample is stirred at 85° C. for 3 hrs under 0.5 arm vacuum to give the product.
Reaction SMILES: [C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 73 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 73% of theory, C28H29N5O3 (483.6); Rf value: 0.15 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=484; (M+H+Na)++=253.7.
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH2:10]([C:14]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[NH:17][C:16](=O)[CH:15]=1)[CH2:11][CH2:12][CH3:13].P(Cl)(Cl)([Cl:30])=O>>[CH2:10]([C:14]1[CH:15]=[C:16]([Cl:30])[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[N:19]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cc(=O)[nH]c(-c2cccc(F)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCCCc1cc(Cl)nc(-c2cccc(F)c2)n1

Procedure:
A solution of N, N-dimethylaniline (0.31 mL) and 6-butyl-2-(3-fluoro-phenyl)-3H-pyrimidin-4-one (0.3 g) in 6 mL phosphorus oxychloride was heated in a sealed tube for 2.5 h at 125° C. The solution was allowed to cool and the phosphorous oxychloride were removed in vacuo. The remaining residue was washed four times with diethyl ether and the combined ether portions were washed with 0.5 M hydrochloric acid, dried over magnesium sulfate, and concentrated in vacuo to yield 4-butyl-6-chloro-2-(3-fluoro-phenyl)-pyrimidine (0.20 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18](=O)[CH2:19]Br)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2].[C:24]([N:27]([CH2:30][C:31]([NH2:33])=[S:32])[CH2:28][CH3:29])(=[O:26])[CH3:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[N:33]=[C:31]([CH2:30][N:27]([C:24](=[O:26])[CH3:25])[CH2:28][CH3:29])[S:32][CH:19]=3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Reactant: CCN(CC(N)=S)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CN(CC)C(C)=O)n3)c(F)cc2c1=O

Procedure:
According to example 30, reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 2-(N-acetyl-N-ethylamino)thioacetamide in ethanol gave 1-ethyl-7-[2-[(N-acetyl-N-ethylamino)methyl]-4-thiazolyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 160°-161° C. which was then hydrolyzed in refluxing 6N hydrochloric acid to afford the title compound, mp 289°-300° C. (dec).