Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH:13]2[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.Br[CH2:26][CH2:27][CH2:28][Cl:29].C(OCC)C>CN(C)C=O>[Cl:29][CH2:28][CH2:27][CH2:26][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[CH2:22][CH2:21][C:16]3([O:17][CH2:18][CH2:19][O:20]3)[CH2:15][CH2:14]2)=[CH:23][CH:24]=1
Reactant: Oc1ccc(CC2CCC3(CC2)OCCO3)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(CC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of potassium carbonate 3.92 g) in a solution of 8-(4-hydroxybenzyl)-1,4-dioxaspiro[4.5]decane (1.41 g) and 1-bromo-3-chloropropane (2.81 mL) in N,N-dimethylformamide (35 mL) is stirred for 20 h at room temperature. Diethyl oxide (210 mL) is added and the suspension is filtered. The filtrate is washed with water (twice 50 mL), dried over magnesium sulfate and concentrated under reduced pressure to give 1.635 g of 8-[4-(3-chloropropoxy)benzyl]-1,4-dioxaspiro[4.5]-decane used without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@@H:13]1[CH2:41][N:16]2[C@H:17]([CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@H:15]2[CH2:14]1.C(N(CC)CC)C.O>ClCCl>[CH:28]([C@H:17]1[N:16]2[CH2:41][C@@H:13]([NH:12][C:2]([O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:3])[CH2:14][C@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H](N)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H](NC(=O)OCc3ccccc3)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of benzyl chloroformate (58 μl) in dichloromethane (0.5 ml) was added dropwise to an ice-cooled solution of tert-butyl (4R,7S,8aS)-7-amino-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate and triethylamine (96 μl) in dichloromethane (2 ml), and the whole was stirred for 2 hours at the same temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected to give tert-butyl (4R,7S,8aS)-4-benzhydryl-7-[(benzyloxycarbonyl)amino]hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (190 mg) as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[O:32][CH:33]([CH3:35])[CH3:34])=[CH:4][CH:3]=1>C(O)=O.[Zn]>[CH:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]1[C:17](=[O:19])[C:18]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:10]([O:32][CH:33]([CH3:34])[CH3:35])[CH:11]=[N:12][C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[O:25]
Reactant: CC(C)Oc1cnc2c(c1C(O)c1ccc(F)cc1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: [Zn]
Solvent: O=CO
Product: CC(C)Oc1cnc2c(c1Cc1ccc(F)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 60 °C
Yield: 79.7 %

Procedure:
To a solution of 5-((4-fluorophenyl)(hydroxy)methyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (128 mg, 0.26 mmol) in HCOOH (5 mL) was added Zn dust (83.5 mg, 1.28 mmol). The reaction was heated at 60° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (4:6) to give 3-(5-(4-fluorobenzyl)-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (89 mg, 81% yield) as a white solid. LCMS: MH+ 430 and TR=2.543 min.
Reaction SMILES: [Br:1][C:2]([Br:10])([Br:9])[CH:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6].[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1>CCOCC.C([O-])(=O)C.[Na+]>[C:14]([O:8][CH:3]([C:2]([Br:10])([Br:9])[Br:1])[CH:4]=[C:5]([CH3:7])[CH3:6])(=[O:15])[CH2:13][C:12]([CH3:11])=[O:16]
Reactant: CC(C)=CC(O)C(Br)(Br)Br
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)CC(=O)OC(C=C(C)C)C(Br)(Br)Br
Yield: 99.1 %

Procedure:
1,1,1-Tribromo-4-methyl-3-penten-2-ol (6.72 g, 0.02 mole) and anhydrous sodium acetate (0.008 g) were melted together at 90°. The temperature of the mixture was then reduced to 80°, and diketene (about 2.6 ml, 0.022 mole) was added dropwise over a 10 minute period. The resulting mixture was heated at 80° for three additional hours. After cooling, the mixture was diluted with ether, and the ethereal solution was washed with 1 N aqueous hydrochloric acid and then ten times with saturated aqueous sodium bicarbonate. The washed mixture was treated with activated charcoal and dried over magnesium sulfate. Evaporation of the ether afforded 3-methyl-1-tribromomethyl-2-butenyl acetoacetate (8.34 g, 99% yield) as an oily residue.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][S:5]([O-])(=[O:7])=[O:6]>P(Cl)(Cl)(Cl)=O>[F:13][C:11]1[CH:10]=[CH:9][C:3]2[CH2:4][S:5](=[O:7])(=[O:6])[NH:1][C:2]=2[CH:12]=1
Reactant: Nc1cc(F)ccc1CS(=O)(=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=S1(=O)Cc2ccc(F)cc2N1
Yield: 31.7 %

Procedure:
2-amino-4-fluorobenzylsulfonate (11.0 g) was added to phosphorous oxychloride (100 ml) at 50° C. and the mixture was heated under reflux for 6 hours. The reaction mixture was concentrated in vacuo and the resulting grease was poured into ice-water mixture. A sodium hydroxide solution was added to the mixture at 0° C. until the mixture was basic. Insoluble material was filtered off and washed with water. The filtrate was treated with aqueous hydrochloric acid solution (pH=2.5). The crude product was separated by filtration. Ethyl acetate was added to the precipitate and the insoluble material was filtered off. The filtrate was concentrated in vacuo, to give 1,3-dihydro-6-fluoro-2,1-benzisothiazole 2,2-dioxide (3.2 g)
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][C:5](=[O:9])[CH2:4][O:3]1.[CH2:10](O)[CH3:11]>S(=O)(=O)(O)O>[CH2:10]([O:9][C:5]1[CH2:4][O:3][CH:2]([CH3:1])[C:7](=[O:8])[CH:6]=1)[CH3:11]
Reactant: CCO
Reactant: CC1OCC(=O)CC1=O
Agent: O=S(=O)(O)O
Product: CCOC1=CC(=O)C(C)OC1

Procedure:
The product from Example 84C (3.0 g, 23 mmol) was dissolved in ethanol (50 mL), treated with concentrated sulfuric acid (5 drops), heated to reflux for 3 hours and concentrated. The residue was purified by chromatography eluting with 10:1 and then 5:1 and then 2:1 hexane:ethyl acetate to provide the title compound as the faster moving isomer.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:3]3[CH2:4][CH2:5][O:1][CH2:2]3)=[CH:14][CH:13]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: O=C(O)c1ccc(C2CCOC2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C3CCOC3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To a solution of 4-(tetrahydrofuran-3-yl)benzoic acid (100 mg, 0.52 mmol) in dichloromethane (20 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.5 mmol), triethylamine (32 mg, 0.7 mmol). The mixture was stirred for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.4 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), the organic layer was concentrated. The residue was purified by preparative-HPLC to give Compound I-83 as a white solid (35 mg, 21%). LRMS (M+H+) m/z: calcd 326.16. found 326. 1H NMR (300 MHz, CD3OD): δ 7.75 (d, J=6 Hz, 2H), 7.36 (d, J=6 Hz, 2H), 6.10 (s, 1H), 4.48 (s, 2H), 4.06 (m, 2H), 4.03 (m, 1H), 3.88 (m, 1H), 3.70 (m, 1H), 2.37 (s, 3H), 2.35 (s, 3H), 2.00 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=O)[CH3:2].[OH-].[K+].B.[Na].Cl>>[CH3:2][CH:1]1[C:4]2[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:8])[O:7]1
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: B
Agent: Cl
Agent: [K+]
Product: CC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.9 %

Procedure:
100.96 g of 2-acetylbenzoic acid (3-1) was dissolved in 500 ml of aqueous solution of 41.37 g of potassium hydroxide, to which 20.35 g of sodium boron hydride was added little by little at a room temperature. The resulting mixture was stirred at a room temperature for 2 days, and thereafter, the resulting mixture was adjusted to pH 1 with concentrated hydrochloric acid and extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, and thereafter, the solvent was distilled off under reduced pressure. The resulting residue was purified by distilling under reduced pressure (117-121° C./3-5 mmHg) to obtain 86.45 g of 3-methylphthalide (3-2).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)=[C:8]([CH2:25][CH2:26][CH3:27])[N:7]2[N:28]=[CH:29][N:30]=[C:6]2[N:5]1[CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1.O1CCCC1.[Cl-].[NH4+]>CO>[OH:37][C@@H:34]1[CH2:35][CH2:36][C@H:31]([N:5]2[C:4](=[O:3])[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:13][CH:12]=3)=[C:8]([CH2:25][CH2:26][CH3:27])[N:7]3[N:28]=[CH:29][N:30]=[C:6]23)[CH2:32][CH2:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium tetrahydroborate (0.55 g) was dissolved in methanol (30 mL), a mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (5.9 g) and methanol (30 mL) was added dropwise at 0° C., and tetrahydrofuran (10 mL) was added. The mixture was stirred at room temperature for 1.5 hr, sodium tetrahydroborate (0.23 g) was added, and the mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.29 g, 13%).
Reaction SMILES: C(O[C:4]1[CH:5]=C(C=[CH:10][C:11]=1C)C=O)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18].BrCCCC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])[CH2:4][CH2:11][CH3:10]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCBr
Product: CCCCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate E10) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with 4-bromo-butane in DMF using K2CO3 as base. MS (ISP): 209.1 [M+H]+.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:17][C:16]([F:19])([F:18])[S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: C1CCNC1
Reactant: O=S(=O)(c1ccc2c(c1)OC(CBr)OC2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1ccc2c(c1)OC(CN1CCCC1)OC2)C(F)(F)F
Temperature: 150 °C
Yield: 48.7 %

Procedure:
A mixture of 2-(bromomethyl)-7-[(trifluoromethyl)sulfonyl]-4H-1,3-benzodioxine (0.40 g, 1.11 mmol), pyrrolidine (0.47 ml, 5.5 mmol), potassiumcarbonate (0.23 g, 1.7 mmol) and ACN (3.0 ml) was heated in a micro wave oven at 150° C. for 15 min. The mixture was filtered and evaporated to dryness. The residue was purified two times on a silica column using EtOAc/MeOH (4:1) and EtOAc/MeOH (9:1) as eluents. The pure fractions were collected and evaporated to afford the title product (0.19 g, 48%). The amine was converted into the fumaric acid salt and crystallized from EtOH/MeOH/DEE. M.p. 184° C. MS m/z (rel. intensity, 70 eV) 351 (M+, 5), 85 (6), 84 (bp), 76 (5), 55 (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([NH:17]S(C(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:7]([O:24][CH3:25])[CH:6]=[CH:5][N:4]=1.Cl.O1CCOCC1>CO>[NH2:17][CH:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][C:7]=1[O:24][CH3:25])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ccnc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) yellow solution of methyl 5-(2,4-dimethoxypyridin-3-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate (653 mg; 1.75 mmol) in MeOH (14 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.90 ml; 3.60 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate as a beige solid. LC-MS (conditions B): tR=0.51 min.; [M+H]+: 269.03 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:21]2[C:20](=O)[C:19]3[C:6](=[CH:7][C:8]4[C:9](=O)[C:10]5[C:15]([C:16](=O)[C:17]=4[CH:18]=3)=[CH:14][C:13]([F:26])=[CH:12][CH:11]=5)[C:5](=O)[C:4]=2[CH:3]=1.CC(CC)[O-].CC(CC)[O-].CC(CC)[O-].[Al+3]>C1(O)CCCCC1>[F:1][C:2]1[CH:23]=[CH:22][C:21]2[C:4](=[CH:5][C:6]3[C:19]([CH:20]=2)=[CH:18][C:17]2[C:8](=[CH:9][C:10]4[C:15]([CH:16]=2)=[CH:14][C:13]([F:26])=[CH:12][CH:11]=4)[CH:7]=3)[CH:3]=1
Reactant: O=c1c2ccc(F)cc2c(=O)c2cc3c(=O)c4ccc(F)cc4c(=O)c3cc12
Agent: CCC(C)[O-]
Agent: [Al+3]
Solvent: OC1CCCCC1
Product: Fc1ccc2cc3cc4cc5cc(F)ccc5cc4cc3cc2c1
Temperature: 100 °C

Procedure:
To a mixture of 0.5 grams of 2,9-difluoropentacene-5,7,12,14-tetrone and 20 mL of cyclohexanol in a flask was added 3.640 grams of aluminum tri(sec-butoxide). The mixture was heated at 100° C. for approximately 12 hours and a blue solid deposited on the sides of the flask. The reaction mixture was centrifuged and the blue solid residue was washed with cyclohexanol, centrifuged twice, and then washed with acetone and collected by filtration. This solid was washed with 50% concentrated HCl and the resulting mixture was centrifuged to give a blue solid. This solid was washed with THF and collected by centrifugation to give 2,9-difluoropentacene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:20])(=[O:19])[NH2:18].[C:21]([OH:33])(=[O:32])[CH2:22][C:23]([CH2:28][C:29]([OH:31])=[O:30])([C:25]([OH:27])=[O:26])[OH:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:19])(=[O:20])[NH2:18].[C:21]([O-:33])(=[O:32])[CH2:22][C:23]([CH2:28][C:29]([O-:31])=[O:30])([C:25]([O-:27])=[O:26])[OH:24]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
1.5 g of 4-(4-chloro-3-sulfamoylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol were reacted in the manner described in example 8 with 1 g of ground citric acid and worked up. Colorless amorphous solid substance, decomposition from 130° C. on, γC=N 1620 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I>O1CCCC1.C(OCC)(=O)C>[CH3:22][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CI
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of methyl 4-[[(tert-butoxycarbonyl)amino]methyl]benzoate (compound obtained in Reference Example 81(1), 2.0 g) in tetrahydrofuran (20 mL) is added sodium hydride (60% dispersion in mineral oil, 0.9 g) under ice-cooling. The mixture is stirred at room temperature for 30 minutes and then to the reaction mixture is added dropwise methyl iodide (2.3 mL). The mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with ethyl acetate, washed with water, and concentrated in vacuo to give methyl 4-[[N-methyl-N-(tert-butoxycarbonyl)amino]-methyl]benzoate (1.9 g, yield; 94%) as a yellow oil. MS (APCI) m/z: 280 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([Cl:10])=[CH:5][C:4]=1[CH2:11]Br.[C:13]1([C:19]([NH2:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:10][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][C:7]=1[F:9])[CH2:2][N:32]([C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:11]2
Reactant: Fc1cc(CBr)c(CBr)cc1Cl
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Fc1cc2c(cc1Cl)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2(b) from 1,2-Bis-bromomethyl-4-chloro-5-fluoro-benzene and triphenylmethylamine. Brown oil.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=O>C1C=CC=CC=1>[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]#[N:10]
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc([N+](=O)[O-])cc1Cl
Yield: 79.7 %

Procedure:
Thionyl chloride (1,000 g, 8.4 m) was then added to the 2-chloro-4-nitrobenzamide (200 g, 1 m) while the mixture was warmed. After addition, the mixture was refluxed for approximately three hours. The excess thionyl chloride was removed by distillation leaving a reaction mixture residue. Benzene (500 ml) was added to the cold reaction mixture residue to extract the reaction product. The extract was washed with diluted sodium hydroxide solution and water until neutralized and then dried over anhydrous sodium sulfate. The benzene solvent was distilled off and the reaction product was crystallized from methanol to yield 2-chloro-4-nitrobenzonitrile (145 g, 79%, mp 73°-75° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]([CH3:8])([CH2:6][CH3:7])[C:4]#[N:5].[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+].CC(N1CCCC1)(C)C(N)C1C=CC=CC=1>C(OCCCC)CCC.C1COCC1.CO>[NH2:5][CH:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([N:2]([CH3:9])[CH3:1])([CH3:8])[CH2:6][CH3:7]
Reactant: CCC(C)(C#N)N(C)C
Reactant: [Li]c1ccccc1
Agent: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCOCCCC
Product: CCC(C)(C(N)c1ccccc1)N(C)C
Yield: 93 %

Procedure:
The title compound (15 g, 93%) was prepared from 2-(dimethylamino)-2-methylbutanenitrile D23 (9.9 g, 0.078 mol) and phenyllithium in dibutylether (87.3 ml of a 1.8M solution; 0.157 mol) in THF (400 ml), followed by reaction with sodium borohydride (5.25 g, 0.138 mol) in methanol (450 ml) in a similar manner to that described in D5. Mass spectrum (Electrospray LC/MS), ES+: Found 207 (MH+). C13H22N2 requires 206. Ret. times 0.83 and 1.10 min.
Reaction SMILES: [CH2:1]([NH2:12])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:13]1[CH2:20][O:19][S:16](=[O:18])(=[O:17])[CH2:15][CH2:14]1>O1CCOCC1>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH2:1][NH:12][CH:13]([CH3:20])[CH2:14][CH2:15][S:16]([OH:19])(=[O:18])=[O:17]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=S1(=O)CCCCO1
Solvent: C1COCCO1
Product: COc1ccc(CNC(C)CCS(=O)(=O)O)cc1OC
Temperature: 25 °C
Yield: 18 %

Procedure:
To a solution of veratrylamine (1.50 g, 9.0 mmol) in 1,4-dioxane (8 mL) was added 1,4-butane sultone (1.21 g, 8.5 mmol) at room temperature. The mixture was then heated at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried on pump. Yield: 18%. 1H NMR (D2O, 500 MHz) δ 6.96 (m, 3H), 4.04 (s, 2H), 3.74 (m, 6H), 2.95 (t, 2H, J=6.8 Hz), 2.80 (t, 2H, J=7.3 Hz), 1.68, (m, 4H). 13C (D2O, 125 MHz) δ ppm 149.19, 148.50, 123.82, 123.36, 113.25, 112.17, 55.91, 50.88, 50.24, 46.41, 24.55, 21.50. ES-MS 302 (M−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]4[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:17][C:15]4=3)[C:10](=[O:28])[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.[Cl:29][C:30]1[S:34][C:33]([CH:35]=O)=[CH:32][CH:31]=1.B.N1C=CC=CC=1C.C(O)(=O)C>CO>[Cl:29][C:30]1[S:34][C:33]([CH2:35][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]5[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[CH:18]=[CH:17][C:15]5=4)[C:10](=[O:28])[CH:9]=[CH:8]3)[CH2:3][CH2:2]2)=[CH:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)ccn(C3CCNCC3)c12
Reactant: O=Cc1ccc(Cl)s1
Agent: B
Solvent: Cc1ccccn1
Solvent: CO
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)ccn(C3CCN(Cc4ccc(Cl)s4)CC3)c12
Yield: 75.6 %

Procedure:
1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (20 mg, 0.050 mmol) in methanol was stirred with 5-chlorothiophen-2-carbaldehyde (6.3 μL, 0.06 mmol), 2-picoline borane (6.4 mg, 0.06 mmol) and acetic acid (100 μL) for one day. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=10/1 (v/v)) to give the title compound as a colorless oil (20 mg, yield 75%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2].C(OCC)(=O)C.Cl.P([S-])(OCC)(OCC)=[S:23]>>[NH2:2][C:1](=[S:23])[CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOP(=S)([S-])OCC
Reactant: CCOC(=O)c1cccc(CC#N)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(CC(N)=S)c1
Yield: 78.8 %

Procedure:
By a method similar to that in Example 178a and using the compound (4.23 g, 22.4 mmol) obtained in Example 180a, 4M hydrogen chloride-ethyl acetate solution (42 mL) and O,O-diethyl dithiophosphate (4.50 mL, 26.8 mmol), the title compound (3.94 g, 79%) was obtained as colorless crystals.