Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[C:11]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=3)[C:13]2=[O:14])=[C:10]([C:24]#[N:25])[C:9]([CH3:26])=[CH:8][CH:7]=1>O1CCCC1>[CH2:1]([NH:4][C:13]([C:15]1[C:20]([C:21]([NH:12][C:11]2[C:6]([Cl:5])=[CH:7][CH:8]=[C:9]([CH3:26])[C:10]=2[C:24]#[N:25])=[O:22])=[CH:19][CH:18]=[C:17]([CH3:23])[N:16]=1)=[O:14])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: Cc1ccc2c(n1)C(=O)N(c1c(Cl)ccc(C)c1C#N)C2=O
Solvent: C1CCOC1
Product: CCCNC(=O)c1nc(C)ccc1C(=O)Nc1c(Cl)ccc(C)c1C#N
Reaction time: 12 h

Procedure:
0.46 g (7.699 mmol) of n-propylamine was added with stirring at 22° C. to a mixture of 0.6 g (1.92 mmol) of the compound from example 11 in 30 ml of tetrahydrofuran and stirred for 12 h. The reaction mixture was concentrated in vacuo and the residue was stirred with diisopropyl ether/diethyl ether 20:1. After filtering off with suction and drying, 0.6 g (82.4% of theory) of the title compound were obtained as colorless crystals of m.p. 129-131° C.
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=1.C(O[Na])(C)(C)C>C1COCC1>[C:9]1([N:8]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:27][N:26]=[CH:25]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C(=N/c1ccccc1)\c1ccccc1
Agent: CC(C)(C)O[Na]
Solvent: C1CCOC1
Product: c1ccc(-c2cncn2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 18 %

Procedure:
To a stirred solution of (E)-N-benzylideneaniline (1.0 mmol) in THF (5 mL) was added TOSMIC (1.1 mmol) and t-BuONa (2.2 mmol). The solution was allowed to stir at room temperature for 5 days. The solvent was evaporated under reduced pressure and the crude product was absorbed on silica gel. After purification by flash column chromatography on silica gel the desired product was obtained in 18% yield. 1H NMR: 7.10-7.16 (m, 2H), 7.16-7.23 (m, 2H), 7.23-7.31 (m, 4H), 7.36-7.42 (m, 3H), 7.73 (s, 1H)
Reaction SMILES: N(OS(=O)(=O)O)=O.N([O-])=O.[Na+].S(=O)(=O)(O)O.[Cl:17][C:18]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([Cl:29])[C:19]=1N.[BrH:30]>C(O)(=O)C.O>[Br:30][C:19]1[C:18]([Cl:17])=[CH:24][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:22][C:21]=1[Cl:29]
Reactant: Br
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=NOS(=O)(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitrosyl sulphuric acid, prepared from sodium nitrite (69 g, 1 mol) and concentrated sulphuric acid (600 ml) was added dropwise with stirring to a cooled solution of 2,6-dichloro-4-trifluoromethylaniline (230 g, 1 mol) in glacial acetic acid (1250 ml) at 15°-20° C. The mixture was stirred for 1 hour at ambient temperature. The diazonium mixture was run slowly into a solution prepared from cuprous bromide (143.4 g, 1 mol), hydrobromic acid (48%, 1 l) and ice (approx. 1000 g) at a rate so as not to exceed a temperature of 35° C. After 1 hour the mixture was steam distilled to give 1 l of distillate which was diluted with water (3 l) and extracted with diethyl ether (2×500 ml). The organic fractions were combined and washed with aqueous sodium hydroxide solution (2M, 2×250 ml) and water (250 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The oily residue was distilled to give 1-bromo-2,6-dichloro-4-trifluoromethylbenzene (256.8 g) as a colourless liquid, b.p. 74°-78° C. at 6 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[CH3:46][N:47]([CH3:53])[C@@H:48]1[CH2:52][CH2:51][NH:50][CH2:49]1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(#N)C.C(N(CC)CC)C>[CH3:46][N:47]([CH3:53])[C@@H:48]1[CH2:52][CH2:51][N:50]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])=[O:29])[CH2:49]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@@H](N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
2.60 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid were dissolved in 20 ml of dry tetrahydrofuran, and the resulting solution was cooled to -20° C. 590 mg of triethylamine and then 704 mg of pivaloyl chloride were added to the solution, after which the resulting mixture was stirred at the same temperature for 5 minutes. 2100 g of (3R)-3-dimethylaminopyrrolidine trifluoroacetate, 788 mg of diisopropylethylamine and 20 ml of dry acetonitrile were then added, in that order, to the mixture, and the mixture was gradually heated and then stirred at 0° C. for 1 hour. The reaction mixture was then filtered, and the solvent was removed by evaporation under reduced pressure. The residue was diluted with ethyl acetate, and the diluted solution was washed with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 3:1 by volume mixture of acetonitrile and methanol as the eluent, to obtain 2.56 g of the title compound as a powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(S(C)(=O)=O)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A27 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (50 μl), methanesulfonyl chloride (10 mg, 0.087 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 2.13 (m, 4H), 2.85 (s, 3H), 3.08 (s, 3H), 3.31 (m, 2H), 3.57 (m, 2H), 4.13 (m, 1H), 5.69 (m, 1H), 7.87 (d, 2H), 7.98 (d, 2H), 8.42 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C17H21N5O7S2 471.09, found 472.3 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16](Br)=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(Cc2ccccc2)CC1
Yield: 50.1 %

Procedure:
1-(1-benzyl-4-piperidinyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate D) (4.3 g, 11.10 mmol), 4-phenoxyphenylboronic acid (Intermediate V) (2.61 g, 12.21 mmol), palladium tetrakistriphenyphosphine(0.77 g, 0.67 mmol) and sodium carbonate(2.82 g, 26.65 mmol) were mixed with ethylene glycol dimethyl ether(100 ml) and water(50 ml). The reaction mixture was heated to reflux overnight. Organic solvent was removed and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed, dried and evaporated. The residue was purified via flash column chromatography using ethyl acetate/methanol (98/2) as mobile phase to give 2.65 g of 1-(1-benzyl-4-piperidinyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 1.99(d, J=11.02 Hz, 2H), 2.25(m, 2H), 2.47 (m, 2H), 3.07(d, J=11.12 Hz), 3.59(s, 2H), 4.80(m, 1H), 5.52(s, 2H), 7.07(d, J=0.67, 1H), 7.15(m, 3H), 7.37(m, 6H), 7.66(d, J=8.51, 2H), 8.37(s, 1H); LC/MS (MH+=477).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:18]C(=O)OC(C)(C)C.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CS(C)=O>[ClH:1].[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[CH:7][C:2]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH2:18])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reaction time: 2 h

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 5.01 g, 27.5 mmol), tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 5 g, 24.97 mmol) and DIPEA (13.08 ml, 74.9 mmol) in DMSO (50 ml) was heated in a sealed vial at 120° C. for 2 hours and then 140° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate (400 ml) and water (200 ml). The organics were washed with water (3×100 ml) and brine (100 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 5-40% ethyl acetate/petrol). To the resulting solid was then added HCl in 1,4-dioxane (4M, 30 ml, 120 mmol) and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo, triturated with diethyl ether and filtered to afford the title compound.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[CH2:20][OH:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C)C=O>[NH2:18][C@@H:19]([CH:22]1[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]1)[CH2:20][OH:21]
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H](CO)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC([C@H](N)CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 4-((1S)-1-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2-hydroxyethyl)piperidine-1-carboxylate (0.95 g, 2.03 mmol) was added 20% piperidine in dimethylformamide (20 mL) all at once. The reaction was stirred overnight at 25° C. The dimethylformamide was evaporated off and the crude residue was subjected to flash chromatography using methylene chloride-methanol-ammonium hydroxide, 95-5-0.1% as eluent. This yielded the amine product as an oil that crystallized upon standing (0.392 g, 80%). MS (+ESI) 245.2 ([M+H]+); 189.2; 150.2.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH2:19][N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: c1cc2nc(N3CCN(C4CC4)CC3)sc2cc1CN1CCCCC1
Temperature: 63 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (500 mg, 1.7 mmol) in MeOH (14 mL) and THF (28 mL) was added piperidine (290 mg, 3.4 mmol), acetic acid (22 mg, 0.4 mmol) and NaCNBH3 (158 mg, 2.7 mmol). The mixture was stirred at 63° C. overnight. The reaction mixture was concentrated under reduced pressure and CH2Cl2 (15 mL) was added to the residue. The mixture was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 332 mg (28%) of 2-(4-cyclopropylpiperazin-1-yl)-6-(piperidin-1-ylmethyl)benzothiazole as a trifluoroacetate salt.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[H-].[Na+].I[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:16]([N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCI
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCn1c(=O)oc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
3,1-Benzoxazin-2,4-(1H)-dione (1.0 g, 6.13 mmol) was dissolved in N,N-dimethylformamide (10 ml), 60% sodium hydride (0.296 g, 7.39 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. 1-Iodopentane (0.97 ml, 7.32 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 1-pentyl-3,1-benzoxazin-2,4-(1H)-dione (0.634 g, 2.72 mmol, yield 44%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([CH2:12][C:13]([O-])=[O:14])#[N:11].[K+].CS(Cl)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:10]([CH2:12][C:13]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:14])#[N:11]
Reactant: N#CCC(=O)[O-]
Reactant: c1ccc2[nH]ccc2c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCC(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(Cyanoacetyl)indole was prepared by suspending indole (11.71 g, 0.10 mmol) and potassium cyanoacetate (24.6 g, 0.2 mmol) in acetonitrile (300 mL), and to this methanesulphonylchloride (7.7 mL, 0.1 mmol) was added. The resulting mixture was stirred at ambient temperature for 1 h, and then sodium carbonate (10 g in 50 mL water) was added. After 5 min, the organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was recrystallised from ethanol (100 mL) to give the desired material as an orange solid (4.31 g), m.p. 226-227°. δH (d6 DMSO) 12.20 (1H, bs), 8.38 (1H, d, J 2.8 Hz), 8.14-8.10 (1H, m), 7.53-7.50 (1H, m), 7.25-7.21 (2H, m) and 4.49 (2H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(O)(CC)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:10]=[C:9]1[NH:11][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: NC(=O)N(c1cccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CCC(C)(C)O
Product: O=C(OCc1ccccc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 35 °C

Procedure:
1108 g (2.85 mol) benzyl 4-[1-(2-chloro-pyridin-3-yl)-ureido]-piperidine-1-carboxylate were refluxed with 720 g (8.57 mol) sodium hydrogen carbonate in 14.5 L tert-amylalcohol. 3 L solvent were distilled off. The reaction mixture was cooled to 35° C. and combined with 11 mL water. Then 13 g (0.058 mol) palladium acetate and 49 g (0.115 mol) 1,4-bis-(diphenylphosphino)-butane (DPPB) were added and the mixture was heated to reflux temperature. It was stirred at 100° C. until the reaction was complete, cooled to RT and 7.5 L of water were added. The organic phase was separated off, washed with 5 L water and then evaporated down. The oily residue was mixed twice with 3 L isopropyl acetate and distilled off. Then the residue was dissolved hot in 7 L isopropyl acetate and slowly cooled to ambient temperature. The solid that crystallised out was suction filtered, washed with 2 L isopropyl acetate and tert.-butyl-methylether and dried at 50° C.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.[CH:29]1([CH2:35][C@@H:36]([CH2:38][OH:39])[NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(CC)CC)C.N1C=CC=CC=1>CS(C)=O>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=1.[CH:29]1([CH2:35][C@@H:36]([CH:38]=[O:39])[NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: N[C@H](CO)CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: N[C@H](C=O)CC1CCCCC1
Reaction time: 0.58 h

Procedure:
To a mixture of the dipeptide alcohol [18a] (2.0 g, 3.65 mmol), triethylamine (1.30 g, 12.85 mmol, 3.5 eq) and DMSO (6 ml) is added at room temperature SO3 pyridine (2.03 g, 12.75 mmol, 3.5 eq) in DMSO (6 ml) and the mixture is stirred for 35 minutes. The reaction mixture is poured on ice, and the resultant aqueous mixture is extracted with ethyl acetate (20 ml×3) The organic layer is subsequently washed with 10% aqueous citric acid, saturated aqueous sodium chloride (×2), 7% aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over MgSO4, and concentrated to dryness in vacuo. The resultant residue is purified with silica gel chromatography (SiO2:100 g, CH2Cl2 :MeOH=95:5) to obtain Boc-His(Ts)-3-cyclohexylalaninal [14a] (1.67 g, 84%) in amorphous powder.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[OH-].[Na+].C([O-])([O-])=O.[K+].[K+]>O.CN1CCCC1=O>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)c2ccccc12
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 92.3 %

Procedure:
A mixture of 4-nitro-1-hydroxynaphthalene (10.0 g, 52.8 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (13.77 g, 74.0 mmol), NaOH (3.0 g, 74.0 mmol), K2CO3 (17.53 g, 126.8 mmol) and 1-methyl-2-pyrrolidinone (400 ml) is heated to 90-100° C. and held for 2-3 hours. The mixture is cooled to 40° C. and water (300 ml) is added. The mixture is cooled to 0° C. and held for 4 hours. The product is collected by filtration, washed with water, cyclohexane and dried under vacuum to constant weight to yield 4-[2-(4-nitro-naphthalen-1-yloxy)-ethyl]-morpholine 14.73 g, 92.6%.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(Cl)(Cl)Cl>N1C=CC=CC=1.CCOCC>[C:17]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[C:15]([Cl:16])=[CH:14][C:5]=3[C:6]=2[CH2:7][CH2:8][CH2:9]1)(=[O:19])[CH3:18]
Reactant: Clc1cc2c(cc1Cl)C1=C(CC2)NCCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(=O)N1CCCC2=C1CCc1cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
6.17 g (0.024 mol) of 8,9-dichloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline are dissolved in 10 ml of pyridine, 9 ml (0.09 mol) of acetic anhydride are added dropwise thereto and the mixture is stirred at room temperature for 17 hours. Chromatography on silica gel with chloroform yields a product which is suspended in ether and removed by filtration. There is obtained 4-acetyl-8,9-dichloro -1,2,3,4,5,6-hexahydrobenzo[f]quinoline with melting point 146-148°.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:6])([OH:5])[OH:4].O.[C:8]([OH:12])(=[O:11])[CH:9]=O>O>[CH2:9]([NH:1][CH2:2][P:3]([OH:5])([OH:4])=[O:6])[C:8]([OH:12])=[O:11]
Reactant: NCP(=O)(O)O
Reactant: O=CC(=O)O
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Yield: 76.1 %

Procedure:
Aminomethylphosphonic acid (5.50 g, 0.05 mol) was dissolved in 50 ml of water maintained at 95°-100° C. Glyoxylic acid hydrate (9.70 g, 0.105 mol) was added in one portion. After 8 hours of reaction time, the water was removed on a rotary evaporator to afford a brown semisolid. Trituration of this semisolid with a small amount of water followed by filtration afforded 6.43 grams of glyphosate as a crude white solid. An additional 1.60 grams of glyphosate was recovered by chromatography of the mother liquor as described in Example 22. The total yield of crude product, which was shown by HPLC to contain 98.87 wt % glyphosate, was 8.03 grams. The actual yield of glyphosate was therefore 94.0%.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][C:5](=O)[CH3:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][CH2:30][OH:31])=[CH:21]1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][C:5]1([CH3:6])[C:21]2[CH2:20][C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]=2[CH2:29][CH2:30][O:31]1
Reactant: OCCC1=CCc2ccccc21
Reactant: CC(=O)CCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCC1(C)OCCC2=C1Cc1ccccc12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-dimethylamino-3-butanone (1.0 g) dissolved in toluene (10 ml), p-toluenesulfonic acid (1.3 g) is added. The suspension is stirred for 10 min. Indene-3-ethanol (1.0 g) in toluene (5 ml) is added to the suspension and the resulting solution stirred for 2 hr. Boron trifluoride etherate (0.25 ml) is added together with ca. 0.5 g of hydrated alkali-aluminum silicate. The mixture is heated at 80° C for 30 min. The mixture is cooled and diluted with water. The organic layer is separated and the aqueous layer extracted with toluene. The organic layers are washed with water. The combined aqueous phase is rendered alkaline with conc.NH4OH and extracted with toluene. The latter extract is treated with charcoal and then concentrated to afford the title compound, identical to the compound of the same name described in Example 284.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH2:23][OH:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH2:23][O:24][CH3:27])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COCc1cc2c(nc1C)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-7-hydroxymethyl-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and methyl iodide.