Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:5]=1[OH:11])=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.[OH-].[K+].Cl>C(O)C.O>[OH:11][C:5]1[CH:6]=[C:7]([I:10])[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:17][C:16]1[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=1
Reactant: CC(=O)c1ccc(I)cc1O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C=CC(=O)c2ccc(I)cc2O)cc(OC)c1OC
Reaction time: 119 h
Yield: 126.6 %

Procedure:
To a stirring suspension of 29 (0.55 g, 2.1 mmol) and 3,4,5-trimethoxy-benzaldehyde (0.66 g, 3.4 mmol, 1.6 equ) in ethanol (10 ml) was added potassium hydroxide (0.25 g, 4.5 mmol, 2.1 equ). The reaction mixture was stirred for 119 hours then diluted with water, acidified (1N HCl) and extracted with ethyl acetate (3×70 ml). The combined organic layers were then washed with saturated aqueous sodium bicarbonate (50 ml), saturated brine (50 ml), 10% sodium bisulfite solution (3×50 ml) and then saturated brine (50 ml) again. The organic layer was then dried (MgSO4) and concentrated in vacuo to give a yellow solid (1.17 g). This solid was heated in methanol, and the undissolved solid collected. The filtrate was concentrated and then heated in methanol again. More undissolved solid was collected. Undissolved solid is 32 (0.50 g, 54%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:12]=[N:13][NH:14][C:3]1=2.C1(=O)O[CH2:18][CH2:17][O:16]1>>[OH:16][CH2:17][CH2:18][C:12]1[C:4]2[O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:2]([CH3:1])[C:3]=2[NH:14][N:13]=1
Reactant: O=C1OCCO1
Reactant: CN1c2ccccc2Oc2cn[nH]c21
Product: CN1c2ccccc2Oc2c(CCO)n[nH]c21
Reaction time: 0.33 h

Procedure:
A mixture of 9.36 g (50 mmols) of 9-methylpyrazolo[4,3-b][1,4]benzoxazine and 13.2 g (150 mmols) of ethylene carbonate is stirred at 180°-200° C. for 10 minutes and at 200°-220° C. for 20 minutes and the mixture is separated by chromatography on silica gel with ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(=O)OC(C)CO1>C(OCC)C>[C:2]1([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1COC(=O)O1
Solvent: CCOCC
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 155 °C
Reaction time: 17 h

Procedure:
Under argon, a solution containing 122 mg of chlorobenzene, 106 mg of sodium carbonate, 157 mg of styrene and 1 ml of propylene carbonate stabilized 0.001 M colloid solution is heated at 155° C. with stirring in a sealed vessel for 17 h. At the end of the reaction, 2 ml of diethyl ether is added, and the mixture is filtered. The yield of isolated trans-stilbene is 15%.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=[N:9][OH:10])[CH2:5][CH2:4]1.P([O-])(O)(O)=O.[K+].[C-:17]#[N:18].[K+]>O>[OH:10][NH:9][C:6]1([C:17]#[N:18])[CH2:7][CH2:8][N:3]([O:2][CH3:1])[CH2:4][CH2:5]1
Reactant: CON1CCC(=NO)CC1
Reactant: [C-]#N
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Product: CON1CCC(C#N)(NO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-methoxy-piperidin-4-one oxime (240 g, 1.66 mol) and potassium dihydrogen phosphate (792.9 g, 5.83 mol) in water (200 ml) at 0-5° C. was added a solution of potassium cyanide (195.1 g, 3.0 mol) in water (200 ml) dropewise (caution!). The reaction mixture was stirred at room temperature overnight (stoppered flask), treated with another portion of potassium dihydrogen phosphate (79.3 g, 0.58 mol) and further stirred at room temperature over another night. The mixture was flushed with nitrogen, the semi-solid removed by filtration and dissolved in ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, all organic layers combined, washed with water and brine, dried over sodium sulfate and concentrated. The residue was triturated with cold diethyl ether, filtered and dried. Yield: 230.8 g of 4-hydroxyamino-1-methoxy-piperidine-4-carbonitrile as a tan solid, mp 130-131° C.
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[O:18]=[C:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O1C2C=CC(O)=CC=2OC1.[CH2:45]1[C:53]2[C:48](=[CH:49][C:50]([OH:54])=[CH:51][CH:52]=2)[CH2:47][CH2:46]1>>[OH:28][C:27]1([C:51]2[CH:52]=[C:53]3[C:48](=[CH:49][C:50]=2[OH:54])[CH2:47][CH2:46][CH2:45]3)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]1=[O:18]
Reactant: Oc1ccc2c(c1)CCC2
Reactant: CCOC(=O)CN1C(=O)C(=O)c2ccccc21
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)CCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with ethyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 5-indanol, the title compound was obtained (84%): 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 7.55 (d, 1H), 7.38 (td, 1H), 7.20 (t, 1H), 6.9 (s, 1H), 6.80 (d, 1H), 6.65 (s, 1H), 4.45 (ABq, 2H), 4.32-4.25 (br, 1H), 4.20 (q, 2H), 2.83 (t, 2H), 2.74-2.65 (m, 2H), 2.06-1.94 (m, 2H), 1.27 (t, 3H); MS (ES+) m/z 350 (M−17), 390 (M+23).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>C(O)(C)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(I)cc3)c2cc1OC
Temperature: 25 °C
Yield: 103.3 %

Procedure:
4-iodoaniline (4.89 g, 22.3 mmol) and 4-chloro-6,7-dimethoxyquinazoline (5.00 g, 22.3 mmol), in isopropanol (200 ml) was heated at reflux for 3 hours before the reaction was allowed to cool to ambient temperature. The solid which had precipitated was collected by suction filtration and washed with diethyl ether (2×50 ml). Drying of this material yielded 4-(4-iodoanilino)-6,7-dimethoxyquinazoline (9.38 g, 95% yield) as a white solid:
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([N:29]2[C:33]([CH3:34])=[C:32]([CH3:35])[C:31]([CH3:36])=[N:30]2)[CH:26]=[CH:25][C:3]=1[O:4][CH2:5][C:6]1[C:11]([C:12]#[C:13][Si](C)(C)C)=[CH:10][CH:9]=[CH:8][C:7]=1[N:18]1[C:22](=[O:23])[N:21]([CH3:24])[N:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CO>[C:12]([C:11]1[C:6]([CH2:5][O:4][C:3]2[CH:25]=[CH:26][C:27]([N:29]3[C:33]([CH3:34])=[C:32]([CH3:35])[C:31]([CH3:36])=[N:30]3)=[CH:28][C:2]=2[CH3:1])=[C:7]([N:18]2[C:22](=[O:23])[N:21]([CH3:24])[N:20]=[N:19]2)[CH:8]=[CH:9][CH:10]=1)#[CH:13]
Reactant: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(C#C[Si](C)(C)C)cccc1-n1nnn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C#Cc1cccc(-n2nnn(C)c2=O)c1COc1ccc(-n2nc(C)c(C)c2C)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-{2-(2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl)-3-trimethylsilylethynyl-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 71) 0.2 g, potassium carbonate 0.7 g, chloroform 5 ml and methanol 5 ml was stirred at room temperature for three hours, and then the resulting mixture was heated to 60° C. and was stirred for three hours. The reaction mixture was filtered, and the filtrate was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-ethynyl-2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 20”) 0.07 g.
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]([C:7]1[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=[C:9]([NH:18][C:19]([NH2:21])=[S:20])[N:8]=1)([CH3:6])[CH3:5]>C(O)C>[CH3:6][C:4]([C:7]1[C:12]([OH:13])=[C:11]([C:14]([CH3:15])([CH3:17])[CH3:16])[N:10]=[C:9]([NH:18][C:19](=[NH:21])[S:20][CH3:1])[N:8]=1)([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1nc(NC(N)=S)nc(C(C)(C)C)c1O
Reactant: CI
Solvent: CCO
Product: CSC(=N)Nc1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Yield: 71.3 %

Procedure:
Methyl iodide (1.05 g, 7.4 mmol) is added to an ethanol (50 mL) solution of N-[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]thiourea (2.0 g, 7.1 mmol) and the mixture is heated at reflux under argon for 2.5 hours. The ethanol is evaporated under reduced pressure and the residue is taken up in 50 mL EtOAc. The EtOAc solution is washed with saturated NaHCO3 (3×50 mL) and 50 mL of brine. Drying over MgSO4 and evaporation of solvent gives an off-white solid. Recrystallization from ether/hexane gives 1.5 g (71%) of N-[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]-S methyl isothiourea; mp 163°-165° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH:37]([CH3:39])[CH3:38])[CH:32]=2)[CH:27]=1>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH:37]([CH3:39])[CH3:38])[CH:32]=4)[CH:27]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: CC(C)Oc1ccc2cc(Br)ccc2c1
Product: CC(C)Oc1ccc2cc(-n3c(C(=O)O)cc4cc(-c5ccc(C(C)(C)C)cc5)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 2-bromo-6-isopropoxynaphthalene.
Reaction SMILES: [NH:1]=[C:2]([C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=12)[S:3][CH2:4][C:5](=O)[C:6](O)=[O:7].ClC(OCC(C)C)=O.C([N:31](CC)CC)C.N>C1COCC1>[CH3:20][N:17]1[C:18](=[O:19])[N:13]2[CH:12]=[N:11][C:10]([C:2]3[S:3][CH:4]=[C:5]([C:6]([NH2:31])=[O:7])[N:1]=3)=[C:14]2[N:15]=[N:16]1
Reactant: CCN(CC)CC
Reactant: Cn1nnc2c(C(=N)SCC(=O)C(=O)O)ncn2c1=O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: Cn1nnc2c(-c3nc(C(N)=O)cs3)ncn2c1=O
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of 3-(imino(3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-yl)methylthio)-2-oxopropanoic acid (0.700 g; 2.5 mmol) in dry THF (30 mL) under nitrogen was added isobutyl chloroformate (0.50 mL; 3.8 mmol), followed by triethylamine (0.53 mL; 3.8 mmol). The mixture was stirred for 1 hour, and then ammonia solution (0.5 M in dioxane; 20 mL) was added, and stirring continued for a further 3 hours. The precipitate was filtered, washed with water (5×20 mL) and diethyl ether (2×15 mL) to yield the title compound as a pale yellow solid (0.223 g; 40%). δH (DMSO-d6) 8.94 (1H, s), 8.42 (1H, s), 7.74 (1H, bs), 7.59 (1H, bs), 3.89 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:24]=[CH:23][O:22][CH:21]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([S:13]CC[Si](C)(C)C)=[CH:8][CH:7]=2)#[N:2].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1.Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:24]=[CH:23][O:22][CH:21]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([SH:13])=[CH:8][CH:7]=2)#[N:2]
Reactant: C[Si](C)(C)CCSc1ccc2c(-c3ccoc3)cc(C#N)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccoc2)c2ccc(S)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
The product from Step 1 (1.8 g) was dissolved in DMF (40 mL) and there was added n-Bu4NF (1M) in THF (15 mL). The resulting mixture was stirred at r.t. for 1.5 h, diluted with 1N aqueous HCl (40 mL) then H2O (300 mL) and filtered to afford the title thiol (1.06 g) as a light orange solid m.p.: 144°-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:38])[O:13][C:14]([OH:37])([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:15]=2[CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:15]([CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[C:14]([O:37][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[O:13][C:12]2=[O:38])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CN(C)CCO
Reactant: COc1ccc(C2(O)OC(=O)C(c3cc(OC)cc(OC)c3)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Solvent: ClCCl
Product: COc1ccc(C2(OCCN(C)C)OC(=O)C(c3cc(OC)cc(OC)c3)C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 125 mL dichloromethane was added 3-(3,5-Dimethoxy-phenyl)-5-hydroxy-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 5.0 g (9.57 mmol), giving a suspension. N,N-dimethylethanol-amine 2.66 g (29.8 mmol) was added, and the mixture was purged with anhydrous HCl gas until saturated. After an hour at room temperature, additional N,N-dimethyl-ethanolamine 1.33 g (14.9 mmol) was added, followed by stirring for 24 hours at room temperature. An additional N,N-dimethylethanolamine 2.66 g (29.8 mmol) was then added, followed by stirring for 24 hours at room temperature. The mixture was evaporated in vacuo, and the residue was suspended in ethyl ether. The ether suspension was washed exhaustively with 4 N NaOH, followed by water and saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to a crude foam, 2.8 g. The crude material was purified by chromatography on 200 g silica gel eluted with 5% methanol in chloroform. The appropriate fractions were evaporated to a glassy solid, 2.31 g. The product was identified by 1H NMR, MS [M--H]+ =594.4 Da.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=4)[NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][NH:34][CH3:35]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][N:34]([CH3:35])[CH3:33])=[CH:27][CH:26]=4)[NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: ClCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3[nH]2)cc1
Solvent: CCO
Product: CN(C)Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3[nH]2)cc1
Reaction time: 0.08 h

Procedure:
A mixture of 220 mg (0.5 mmol) crude (4-benzyloxy-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine in 15 ml absolute ethanol is treated with 0.8 ml (5 mmol) of a 33% solution of dimethylamine in ethanol (Fluka, Buchs, Switzerland) and then heated under reflux for 1 h. The resulting solution is cooled and the solvent evaporated. The residue is dissolved in a mixture of dichloromethane and ethanol (95:5), washed with water, dried over sodium sulfate and the solvent evaporated. The solid material is then suspended in ether stirred for 5 min and filtered. Purification of the crude material through flash chromatography using dichloromethane/ethanol 9:1 plus 1% conc. ammonia gives the title compound; m.p. 272-274° C.; MS-ES+: (M+H)+=450.
Reaction SMILES: [C:1](=O)([S:3][CH2:4][P:5]([O:11][CH:12]([CH3:14])[CH3:13])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:2].C[O-].[Na+].Br[CH:20](C)C>CO>[CH:1]([S:3][CH2:4][P:5](=[O:6])([O:11][CH:12]([CH3:14])[CH3:13])[O:7][CH:8]([CH3:10])[CH3:9])([CH3:20])[CH3:2]
Reactant: CC(C)Br
Reactant: CC(=O)SCP(=O)(OC(C)C)OC(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)OP(=O)(CSC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of S-(diisopropoxyphosphoryl)methyl ethanethioate (1.00 g, 3.93 mmol; Example 206, Step A) in methanol (39.3 mL) at 0° C. was added sodium methoxide (7.87 mL, 3.93 mmol), followed by 2-bromopropane (0.44 mL, 4.72 mmol). The reaction was stirred at 25° C. for 16 hours. The reaction solvent was removed in vacuo and the crude material was partitioned between water and EtOAc (2×) and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (40 g column, eluent: 0 to 75% DCM/hexanes) provided the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([C:12](O)=[O:13])[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[CH2:8][O:7][C:6]=2[CH:19]=1.[CH:20]([C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([C:12]([NH:25][C:24]3[C:26]([CH:30]([CH3:31])[CH3:32])=[CH:27][CH:28]=[CH:29][C:23]=3[CH:20]([CH3:22])[CH3:21])=[O:13])[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[CH2:8][O:7][C:6]=2[CH:19]=1
Reactant: O=C(O)C1c2ccccc2COc2cc(Br)ccc21
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1c2ccccc2COc2cc(Br)ccc21
Yield: 73.4 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.40 g of Compound K in place of Compound A and 0.78 g of 2,6-diisopropylaniline in place of aniline to obtain 1.54 g of Compound 29.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][NH:20][CH2:21][CH:22]1[CH2:25][NH:24][CH2:23]1>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:24]3[CH2:25][CH:22]([CH2:21][NH:20][CH3:19])[CH2:23]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CNCC1CNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(CNC)C3)nc21
Temperature: 5 °C
Yield: 26.9 %

Procedure:
A suspension of 0.81 g (3.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid, 0.9 g (9.0 mmole) of N-methyl-3-azetidinemethanamine and 30 mL of acetonitrile was refluxed for six hours. The reaction was cooled to 5° C. The filtered solids were washed with acetonitrile, ether, and dried in vacuo. The dried solid was suspended in 70 mL of water and made basic to pH 11.0 after filtering through a fiber glass pad to clarify, the filtrate was acidified to pH 7.4 with 1.0M hydrochloric acid. The resulting precipitate was removed by filtration, washed successively with water, 2-propanol, ether and dried in vacuo to give 270 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-azetidinyl]-4-oxo-1,8 -naphthyridine-3-carboxylic acid, mp 180°-182° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[C:24]1([CH2:23][N:3]2[CH:4]=[CH:5][C:6](=[O:16])[C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:2]2[CH3:1])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1Cc1ccccc1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
73 g of the product of Example 2 were dissolved in 4 liters of ethanol (dry). 25 g K2CO3 powderized and 70 g benzylbromide were added. After refluxing for 4 hours and filtration, the solvent was distilled off and the residue extracted with 4 liters of hot petroleum ether in 3 parts. After cooling to room temperature and filtration the petroleum ether filtrate was concentrated to 2 liters and cooled to -10° C. 31 g of white crystals of the title compound of Example 3 were obtained. The formed title compound 3A was insoluble in petroleum ether at room temperature white crystals. 70% of total yield.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:19]([N:22]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:23][C@H:24]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH3:25])[CH:20]=[CH2:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH2:3]([N:26]([C@H:24]([CH3:25])[CH2:23][N:22]([CH2:19][CH:20]=[CH2:21])[C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])(=[O:28])=[O:29])[CH:2]=[CH2:1]
Reactant: C=CCO
Reactant: C=CCN(C[C@@H](C)NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCN(C[C@@H](C)N(CC=C)S(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C

Procedure:
0.4 mL of allyl alcohol and 1.5 mL of diisopropyl azodicarboxylate were added dropwise at room temperature in an argon atmosphere to a solution containing 1 g of the compound obtained in Step 2 and 2 g of triphenylphosphine dissolved in 100 mL of tetrahydrofuran, and then reacted for 16 hours. The reaction solution was diluted with water, followed by extraction with ethyl acetate (100 mL×2). Then, the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (acetone:hexane=1:2) to obtain 550 mg of the compound of interest as a colorless oil (50%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[C:13]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(N)cc1OC1CCN(C)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(F)cc2)cc1OC1CCN(C)CC1
Reaction time: 20 h
Yield: 86.2 %

Procedure:
Add 4-fluorobenzoyl chloride (222 mg, 1.4 mmol) to a solution of 4-Methyl-3-(1-methyl-piperidin-4-yloxy)-phenylamine (preparation 34, 280 mg, 1.27 mmol) in pyridine (10 mL), beat at 55° C. for 20 hr. Remove volatiles in vacuo, dissolve the residue in CH2Cl2, wash with 0.1N NaOH and saturated NaCl solution sequentially, dry over Na2SO4, filter and concentrate to give a residue. Chromatography on a silica gel column eluting with 6% 2M NH3-methanol in CH2Cl2) provides the title compound as a colorless oil (375 mg, 86%). Mass spectrum (ion spray): m/z=343.3 (M+1); 1H NMR (CDCl3, ppm): 7.94 (s, br, 1H), 7.88 (m, 2H), 7.85 (s, br, 1H), 7.12 (m, 3H), 6.87 (dd, 1H), 4.39 (m, 1H), 2.62 (m, 2H), 2.33 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 2.06-1.83 (m, 4H); Anal calcd for C20H23FN2O2.HCl H2O: C, 60.53; H, 6.60; N, 7.06. Found: C, 60.77; H, 6.20; N, 7.10.