Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([CH2:19][C:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][C:22]([OH:24])=O)=[CH:11][C:10]=1[Cl:35].[NH:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[NH:44][C:43]2=[O:52])[CH2:38][CH2:37]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([CH2:19][C:20]([CH2:21][C:22](=[O:24])[N:36]2[CH2:37][CH2:38][CH:39]([N:42]3[CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[NH:44][C:43]3=[O:52])[CH2:40][CH2:41]2)([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11][C:10]=1[Cl:35]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CCOC(=O)C(CC(=O)O)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.2 mL (23.0 mmol) of triethylamine were added dropwise to a solution of 8.00 g (19.0 mmol) of 4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoic acid, 4.39 g (19.0 mmol) of 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one, 6.00 g (18.0 mmol) of TBTU and 2.75 g (18.0 mmol) of HOBT in 100 mL of THF and the mixture was stirred for 16 h at RT. The solid formed was filtered off, washed with diethyl ether and dried i. vac.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:19]=1[F:20])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH3:21][C:22]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:19]=1[F:20])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([N+:29]([O-:31])=[O:30])[C:22]=2[CH3:21])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Oc2ccc(C=O)cc2)ccc1F
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1F

Procedure:
The product from Example 305D and 2-methyl-3-nitroaniline were processed as in Example 6A to provide the title compound. MS (ESI−) m/z 407 (M−H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:6].C(N(CC)CC)C.[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][BH:31][O:30]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:19]1[CH:18]=[CH:17][C:4]([C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:6])=[CH:3][C:2]=1[B:31]1[O:32][C:33]([CH3:35])([CH3:34])[C:29]([CH3:36])([CH3:28])[O:30]1
Reactant: Cc1ccc(C(=O)NCCCN2CCOCC2)cc1I
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NCCCN2CCOCC2)cc1B1OC(C)(C)C(C)(C)O1

Procedure:
The procedure used in Example 3: step b was followed using 3-iodo-4-methyl-N-(3-morpholin-4-yl-propyl)-benzamide ((Example 301: step a) 695 mg, 1.79 mmol), PdCl2(PPh3)2 (63 mg, 0.09 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL). Analogous aqueous workup and purification by SiO2 flash column chromatography (0–10% MeOH in DCM) yielded the title compound contaminated with the product resulting from halide reduction (653 mg, 94%). The material was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[O:9])=[C:6]([OH:22])[CH:5]=1)([O-])=O.[H][H]>[Pd].[Cr].[Co].O1CCOCC1>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[O:9])=[C:6]([OH:22])[CH:5]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1O
Reactant: [H][H]
Agent: [Co]
Agent: [Cr]
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc(NC(=O)c2ccc(N)cc2O)cc1

Procedure:
4,4'-Dinitro-2-hydroxybenzanilide (20.0 g, 0.066 mol), dioxane (300 mL), and 10 percent Pd/C were placed in a 600 mL Hastelloy C Parr Reactor. The material was hydrogenated at 100° C. and 150 psi (1033 kPa) of hydrogen for 16 hours, after which the reactor was allowed to cool and hydrogen was vented off. The catalyst was filtered and the major portion of the solution was set aside for Step C, while dioxane was removed in vacuo from a small portion of the solution to give a product having a melting point of 235° C. to 238° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 59.2 %

Procedure:
A mixture of 0.0406 g (0.00013 mole) of 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38), 0.0191 g (0.000138 mole) of 4-aminobenzoic acid, 0.7 mL of ethanol, 2.8 mL of water and 3 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled and the white precipitate which formed was collected by filtration to give 0.0315 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-50a) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH3:34][C@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][O:44][C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:33])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:36]1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: C[C@@H]1CN(CCO)CCN1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)[C@H](C)C5)ccn34)c12
Temperature: 95 °C
Yield: 33 %

Procedure:
7-Fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 1, Step A), 0.300 g, 0.678 mmol), (R)-2-(3,4-dimethylpiperazin-1-yl)ethanol (0.536 g, 3.39 mmol), and potassium t-butoxide (0.456 g, 4.07 mmol) were combined in t-butanol in a pressure tube. The tube was sealed and warmed to 95° C. for 16 hours, then allowed to cool to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (10% MeOH/DCM/0.5% NH4OH) of the crude material followed by trituration with ether gave 136 mg (33%) of the title compound. MS (APCI), positive scan, m/z=581.1 (M+H). [α]D=−5.3° (c=1.0, CHCl3).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:36]([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:42])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(O)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1cc(Cl)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 60771136 %

Procedure:
To 10 ml of DMF, 0.8 g (2.2 mmol) of 3-(2-chloro-4-hydroxy-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone, 0.42 g (3.0 mmol) of potassium carbonate and 0.56 g (3.3 nmol) of ethyl 2-bromopropionate were added, followed by heating and stirring at 60° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.90 g (yield: 94%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:23])=[CH:6][C:7]=1[C:8]([CH3:22])([CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:9].[Br-:24].[Li+]>CS(C)=O>[Br:24][CH2:10][C:8]([C:7]1[CH:6]=[C:5]([CH3:23])[N:4]=[N:3][C:2]=1[Cl:1])([CH3:22])[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)c2cc(C)nnc2Cl)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CS(C)=O
Product: Cc1cc(C(C)(C)CBr)c(Cl)nn1

Procedure:
A 0.6 g. portion of 3-chloro-4-(1-methyl-1-p-toluenesulfonyloxymethylethyl)-6-methylpyridazine was dissolved in 10 ml. of dimethylsulfoxide and was reacted with 0.3 g. of lithium bromide at 110°, as described in examples above, to obtain 200 mg. of the desired product, a light yellow oil, the identity of which was confirmed by mass spectroscopy. A molecular ion of weight 262 was observed, as was the ion of weight 169 which resulted from loss of the bromomethyl group from the compound.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[C:1]([NH:3][C:4]([NH:20][CH2:19][CH2:18][NH2:21])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: NCCN
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCN

Procedure:
Reaction of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea with excess ethylenediamine at room temperature afforded the title compound m.p. 164°-167° (from acetonitrile-ethanol)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]>CN(C)C=O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH:5]([P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:14]
Reactant: Clc1ccccc1CBr
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1Cl)P(=O)(OCC)OCC
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a stirred solution of ethyl(diethoxyphosphoryl)acetate (10.0 g, 44.6 mmol) in N,N-dimethylformamide (100 mL) was added 60% sodium hydride in mineral oil (1.96 g, 49.1 mmol) at 0° C. and the mixture was stirred for 1 h at the same temperature. To the mixture was added 1-(bromomethyl)-2-chlorobenzene (6.35 mL, 49.1 mmol) at 0° C. and the resulting mixture was stirred for 18 h at the room temperature. The reaction mixture was quenched by the addition of water, then extracted with diethyl ether (200 mL×2), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (500 g) eluting with hexane/ethyl acetate (1/1) to afford 14.6 g (93%) of the title compound as a colorless oil:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH2:26][NH:27][CH2:28][CH2:29][CH:30]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:27]1[CH2:28][CH2:29][CH:30]=[C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH2:26]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C1=C(c2ccccn2)CNCC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CCC=C(c2ccccn2)C1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.9 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.83 g, 3.3 mmol) and 1′,2′,5′,6′-tetrahydro-2,3′-bipyridine (3.51 g, 21.9 mmol) were dissolved in acetonitrile (50 ml), and lithiumperchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.87 g of the intended substance (yield 61.9%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1.[Si](Cl)(Cl)(Cl)Cl.Cl>O.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11]([NH:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cc(Cl)ccc1OCc1ccccc1
Agent: Cl
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nnn[nH]1)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
Dry 2-benzyloxy-5-chlorobenzoic acid (1.15 g) was treated, with stirring, with dry pyridine (20 ml) and anhydrous 5-aminotetrazole (3.72 g). The mixture was stirred at 25° C. and treated dropwise with silicon tetrachloride (0.45 g), and the mixture was then stirred at 25° C. for 20 hours. The resulting clear yellow solution was cautiously poured into a mixture of ice and water (50 ml) and the mixture was acidified to pH 1 by treatment with concentrated hydrochloric acid. The white precipitated solid was filtered off, washed with water, with ethanol and with diethyl ether, and recrystallized from a mixture of dimethylformamide and water to give 2-benzyloxy-5-chloro-N-(tetrazol-5-yl)benzamide, (0.29 g), m.p. 256°-257° C. (with decomposition).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([CH2:28][Cl:27])[CH:30]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Reactant: O=C(Cl)c1cccc(CCl)c1
Product: O=C(Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1)c1cccc(CCl)c1
Yield: 80 %

Procedure:
The title compound was prepared from (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol and 3-chlormethylbenzoylchloride in 80% yield as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:12][CH:11]([CH2:13][CH2:14][OH:15])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([O:15][CH2:14][CH2:13][CH:11]2[CH2:12][N:9]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])[CH2:10]2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: CC(c1ccccc1)N1CC(CCO)C1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CC(c1ccccc1)N1CC(CCOc2ccc([N+](=O)[O-])cc2)C1

Procedure:
The title compound is prepared according to the procedures of Example 3 from 1-(1-phenylethyl)-3-azetidine ethanol and 4-nitrophenol.
Reaction SMILES: [CH3:1]S(OCC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.C([S-])CC.[Na+].F[C:26](F)(F)[CH2:27][S:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>>[CH3:26][CH:27]([S:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CSCC(F)(F)F)CC1
Agent: CCC[S-]
Agent: [Na+]
Product: CC(C)SCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 60 %

Procedure:
tert-Butyl 4-[(propan-2-ylsulfanyl)methyl]piperidine-1-carboxylate was prepared from tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) and sodium propanethiolate (0.161 g, 1.636 mmol) according to the method described for Intermediate 183 to afford the title compound (0.180 g, 60%). Method B HPLC-MS: MH+ requires m/z=274 Found: m/z=218 (M-tert-Bu), Rt=2.51 min.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH2:7][CH3:8])[CH2:4][NH2:5].Br[CH2:10][CH:11]1[O:16][CH2:15][CH2:14][CH2:13][O:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:15][O:16][CH:11]([O:12][CH2:13][CH3:14])[CH2:10][NH:5][CH2:4][CH:3]1[O:2][CH2:1][CH2:8][CH2:7][O:6]1
Reactant: BrCC1OCCCO1
Reactant: CCOC(CN)OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CNCC1OCCCO1)OC
Temperature: 25 °C

Procedure:
2-Methoxy-2-ethoxyethylamine (0.11 mole), 2-bromomethyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](N1C=CN=C1)=[O:4].[CH3:12][C:13]1[N:14]=[C:15]([Si](C)(C)C)[O:16][CH:17]=1.O>C(OCC)C>[CH3:12][C:13]1[N:14]=[C:15]([C:3](=[O:4])[C:2]([F:11])([F:10])[F:1])[O:16][CH:17]=1
Reactant: Cc1coc([Si](C)(C)C)n1
Reactant: O=C(n1ccnc1)C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: Cc1coc(C(=O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Trifluoroacetylimidazole (10 g) was added dropwise to 4-methyl-2-trimethylsilyloxazole (J. Chem. Soc., Chem. Commun., 1984, 258) (9.95 g) in diethyl ether (100 ml) at 0° C. under an atmosphere of dry nitrogen. The mixture was stirred overnight at room temperature. Water was added and the organic layer was separated, washed, dried and evaporated. Flash chromatography gave the title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH:16]=O)=[CH:6]1)(=[O:4])=[O:3].C([CH2:25][NH2:26])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][S:2]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][NH:26][CH3:25])=[CH:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)n1cc(C=O)cc1-c1ccccc1
Reactant: NCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCc1cc(-c2ccccc2)n(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To a solution (5 mL) of 1-(methylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (160 mg) in tetrahydrofuran was added benzylmethylamine (117 mg), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (435 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL), 10% palladium carbon (50% water-containing product, 200 mg) and 1 mol/l hydrochloric acid (1 mL) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction mixture was filtrated; and the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→ethyl acetate) to give the title compound as a colorless oil (yield 62 mg, 37%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[CH:18]=[CH:17][C:13]3=[N:14][O:15][N:16]=[C:12]3[CH:11]=2)=[O:9])[CH2:2]1.[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH3:21][N:7]([CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)[C:8]([C:10]1[CH:18]=[CH:17][C:13]2=[N:14][O:15][N:16]=[C:12]2[CH:11]=1)=[O:9]
Reactant: O=C(NC1CCCOC1)c1ccc2nonc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc2nonc2c1)C1CCCOC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
N-(Tetrahydro-2H-pyran-3-yl)-[2,1,3]-benzoxadiazole -5-carboxamide (371 mg, 1.5 mmol) was added to a suspension of sodium hydride (216 mg, 9 mmol) in dry DMF (5 ml), followed by methyl iodide (1.0 ml) and the mixture was stirred at 20° C. for 1 hour. The solvent was evaporated under vacuum, dichloromethane (30 ml) was added and the organic phase was washed with 1N HCl (100 ml) and NaHCO3 solution (100 ml). The aqueous was re-extracted with dichloromethane (100 ml), the organics dried over magnesium sulfate and concentrated under vacuum to give the title compound as a white solid after trituration with diethyl ether (186 mg). Mp: 134-135° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, 1H, J=9.0 Hz); 7.83 (s, 1H); 7.40 (d, 1H, J=9.0 Hz); 4.70-3.20 (m, 4H), 3.01 (sb, 3H) and 2.10-1.50 ppm (m, 4H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:27]2
Reactant: OCc1ccc2c(c1)CNC2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cn(C2CC2)c2nc(N3Cc4ccc(CO)cc4C3)c(F)cc2c1=O
Yield: 22.3 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 298 mg of 5-hydroxymethylisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in a similar manner as in Example 107 to produce 88 mg of 7-(5- hydroxymethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.