Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15]C.BrC1N=C(C)C(NC2C3C(=CC=CC=3)CC2)=NC=1C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:28])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[N:13][C:14]=1[CH3:15]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: Cc1nc(NC2CCc3ccccc32)c(C)nc1Br
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1NC1CCc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.94, 2.29, 2.39, 2.80, 2.96, 3.08, 4.64, 5.83, 7.33, 7.51; MS (ESI+) for C21H19Cl2N3 m/z 385.30 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][C:7](Br)=[O:8].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)#[N:11]>ClCCl>[Br:5][CH2:6][C:7]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:10]#[N:11])=[CH:17][CH:16]=2)=[CH:23][CH:22]=1)=[O:8]
Reactant: O=C(Br)CBr
Reactant: N#Cc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(C(=O)CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.68 g aluminium chloride (35.15 mmol) are dissolved in 45 ml dichloromethane and treated dropwise with 3.38 g (16.74 mmol) bromoacetyl bromide at 0° C. After 30 min 3 g (16.74 mmol) 4-cyanobiphenyl, dissolved in 15 ml dichloromethane, are added dropwise. The reaction mixture is stirred overnight at ambient temperature, added to ice-water and extracted 2 times with dichloromethane. The organic phase is washed with water and brine, dried and evaporated. The residue is triturated with petrol ether, filtered and dried. Yield: 4.24 g (83%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2)C1C=CC=CC=1>C(O)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2
Reactant: CC(C)C(O)(c1ccc2cc(OCc3ccccc3)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1c[nH]cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
1-(6-Benzyloxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (0.9 g) was dissolved in acetic acid (20 ml), and to the solution was added 10% palladium carbon (0.25 g). The mixture was stirred at 50° C. for 2 h under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluent; dichloromethane-methanol=10:1). Crystallization from methanol-ethyl acetate-diisopropyl ether gave the titled compound (0.30 g) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]1[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=1>CN(C)C=O>[N:15]1[C:16]2[NH:1][C:2]3[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=3[O:12][C:17]=2[N:18]=[CH:19][CH:14]=1
Reactant: Clc1nccnc1Cl
Reactant: COC(=O)c1ccc(O)c(N)c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)Nc1nccnc1O2
Temperature: 160 °C
Yield: 74.2 %

Procedure:
21.3 g of methyl 3-amino-4-hydroxybenzoate and 23 g of 2,3-dichloropyrazine were added to 40 ml of dry N,N-dimethylformamide and the resulting mixture was stirred under heating to 160° C. for 6 hours. Then the reaction mixture was brought back to room temperature and the crystals thus precipitated were taken up by filtration and washed with ethyl acetate. Thus 23 g of the title compound was obtained as brown crystals.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[C:5]([F:14])[CH:4]=1)#[N:2].ClC1C=C(C#N)C=CC=1C(OCC)=O>>[F:14][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:13]=[CH:12][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1ccc(C#N)cc1F
Agent: CCOC(=O)c1ccc(C#N)cc1Cl
Product: N#Cc1ccc(C(=O)O)c(F)c1
Yield: 100 %

Procedure:
In the same manner as in Example II-(41-2) except for using 0.58 g (3.0 mmol) of ethyl 4-cyano-2-fluorobenzoate tit in place of ethyl 2-chloro-4-cyanobenzoate, the reaction was carried out similarly to obtain 0.50 g (3.0 mmol) of the title compound as white crystal.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]([NH:28][C@@H:29]([C:37](O)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O.O.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[C:24]([O:23][C:21]([NH:28][C@H:29]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]([NH:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20])=[O:38])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1C(=O)C(NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3(R,S)-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (4 g, 14.8 mmol) in anhydrous dimethylformamide (35 ml), under an atmosphere of nitrogen, was added in succession Boc-D-phenyl-alanine (4.11 g, 15.4mmol), 1-hydroxybenzotriazole trihydrate (2.09 g, 15.4 mmol) and 1-ethyl-3-[3-(dimethylamino) propyl]carbodiimide hydrochloride (2.97 g, 15.4 mmol). Triethylamine (2.16 ml, 15.4 mmol) was then added and the resulting suspension was stirred at ambient temperature for 20 min. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and 10% citric acid solution (50 ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with 10% sodium hydroxide solution (50 ml), water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, using 1:1 petrol:ethyl acetate as the eluant, to afford the product (7.26, 95%) as a pale yellow solid. mp 95°-98° C. 1H NMR (360 MHz, CDCl3) δ 0.99-1.11 (1H, m), 1.16-1.72 (7H, m), 1.40 (9H, s), 1.83-1.92 (1H, m), 1.98-2.06 (1H, m), 2.73-2.83 (1H, m), 3.10-3.24) (2H, m), 3.38 (3H, s), 4.53 (1H, brs), 4.98 (1H, brs), 5.28-5.34 (2H, m), 7.19-7.32 (7H, m), 7.49-7.58 (2H, m).
Reaction SMILES: [CH2:1]([N:3]([CH3:14])[C:4]1[C:12]([CH3:13])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)[CH3:2].[CH:15](NC)(C)C>>[CH:1]([N:3]([CH3:14])[C:4]1[C:12]([CH3:13])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)([CH3:15])[CH3:2]
Reactant: CNC(C)C
Reactant: CCN(C)c1ncc(C(=O)O)cc1C
Product: Cc1cc(C(=O)O)cnc1N(C)C(C)C

Procedure:
The title compound is prepared in analogy to 6-(ethyl-methyl-amino)-5-methyl-nicotinic acid using N-isopropyl-methyl-amine; LC-MS: tR=0.58 min, [M+1]+=209.10; 1H NMR (D6-DMSO): δ 1.23 (d, J=6.5 Hz, 6H), 2.40 (s, 3H), 2.97 (s, 3H), 4.22 (hept, J=6.8 Hz, 1H), 8.07 (s, 1H), 8.43 (d, J=2.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[C@H:13]([C:26]([O:28]CC)=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH2:46][CH2:47][NH:48][CH2:49][CH:50]=3)=[CH:41][C:40]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][NH:14][C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH:45]3[CH2:46][CH2:47][NH:48][CH2:49][CH2:50]3)=[CH:41][C:40]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:35]([F:36])([F:38])[F:37])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C5=CCNCC5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(C3CCNCC3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate using the LiOH general method provided the title compound as an off-white solid.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[C:29]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:28][CH:27]=[CH:26][N:25]=4)[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[C:29]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:28][CH:27]=[CH:26][N:25]=4)[C:19]([C:34]([F:37])([F:35])[F:36])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
Formaldehyde (37 wt % in H2O; 16.5 μL, 0.222 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide (32) (22 mg, 0.044 mmol) in anhydrous methanol (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (94.0 mg, 0.444 mmol) was then added in one portion and the reaction was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (25 mL) and sat. aq. NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL), the combined organic layers were washed with water (25 mL), brine (25 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to yield a white solid. The solid was suspended in DCM (5 mL) and cyclohexane (20 mL) and filtered to afford the title compound (33) (16 mg, 72%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 8.64 (s, 1H), 8.36 (dd, J=4.8, 1.7 Hz, 1H), 7.59 (dd, J=7.7, 1.2 Hz, 3H), 7.53 (s, 1H), 7.20-7.13 (m, 3H), 7.00 (s, 1H), 3.53 (s, 2H), 3.24 (s, 4H), 2.91 (d, J=10.6 Hz, 2H), 2.47-2.39 (m, 1H), 2.24 (s, 3H), 2.12-1.99 (m, 2H), 1.78-1.59 (m, 4H). LCMS Method C: rt 1.51, 1.579 min; m/z 499 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33]Br)([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:46])([F:45])[C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33][O:44][C:41]1[CH:42]=[CH:43][C:38]([C:37]([F:36])([F:45])[F:46])=[CH:39][CH:40]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CBr
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1COc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.4 %

Procedure:
A 50 mL round bottomed flask was charged with 3-[2-bromomethyl-4-(tert-butyldiphenylsilanyloxy)phenyl]propionic acid tert-butyl ester (1.0 g, 1.81 mmol), anhydrous DMF (10 mL), and then 4-trifluoromethylphenol (0.44 g, 2.7 mmol) and cesium carbonate (0.88 g, 2.7 mmol). The reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 18 h and concentrated. The residue was diluted with EtOAc (100 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to a yellow oil. The crude residue was purified using radial (EtOAc:hexanes 15:85 to 50:50) to give a yellow oil (0.66 g, 58%). MS (ES) m/e 635 (M+1).
Reaction SMILES: CS[CH2:3][C:4]1[NH:18][C:17]2[C:19]3[C:5]=1[CH2:6][C@@H:7]1[C:12]([C:13]=3[CH:14]=[CH:15][CH:16]=2)=[CH:11][C@H:10]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:9][N:8]1[CH2:28][CH2:29][CH3:30].[C:31](C(C(C([O-])=O)O)O)(O)=O>N1C=CC=CC=1>[CH2:25]([N:22]([CH2:23][CH3:24])[C:21]([NH:20][C@H:10]1[CH2:11][C@H:12]2[C@@H:7]([CH2:6][C:5]3[C:19]4[C:17](=[CH:16][CH:15]=[CH:14][C:13]2=4)[NH:18][C:4]=3[CH2:3][CH3:31])[N:8]([CH2:28][CH2:29][CH3:30])[CH2:9]1)=[O:27])[CH3:26]
Reactant: CCCN1C[C@@H](NC(=O)N(CC)CC)C=C2c3cccc4[nH]c(CSC)c(c34)C[C@H]21
Reactant: O=C([O-])C(O)C(O)C(=O)O
Solvent: c1ccncc1
Product: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cccc4[nH]c(CC)c(c34)C[C@H]21

Procedure:
3-(9,10-didehydro-2-methylthiomethyl-6-n-propyl-8α-ergolinyl)-1,1-diethylurea, yield 50% as hydrogen tartrate, [α]D +169° (c=0.5 in pyridine).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:15][S-:16].[Na+].[ClH:18]>CN(C)C=O>[ClH:18].[CH3:15][S:16][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: C[S-]
Reactant: N#Cc1cc(OC(F)(F)F)ccc1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(OC(F)(F)F)cc1CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) A mixture of 2-fluoro-5-(trifluoromethoxy)benzonitrile (6.55 g) and sodium methanethiolate (2.46 g) was stirred in N,N-dimethylformamide (50 ml) at room temperature for 3 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. A solution of the obtained residue in tetrahydrofuran (20 ml) was added at 0° C. to a suspension of lithium aluminum hydride (1.45 g) in tetrahydrofuran (250 ml). The mixture was stirred at room temperature for 2 hr, and treated with sodium sulfate 10 hydrate. The mixture was further stirred at room temperature for 30 min, and the inorganic substance was filtered off through celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (10 ml) was added. The mixture was crystallized from methanol-ethyl acetate to give 1-[2-(methylsulfanyl)-5-(trifluoromethoxy)phenyl]methanamine hydrochloride (4.3 g).
Reaction SMILES: [N+:1]([O-])(O)=O.S(=O)(=O)(O)O.[CH2:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>>[CH2:10]1[C:18]2[C:13](=[C:14]([NH2:1])[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: c1ccc2c(c1)CCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1cccc2c1CCC2
Temperature: 5 °C
Reaction time: 16 h

Procedure:
24 ml (349 mmol) 65% nitric acid are cooled to 0-5° C. 28 ml (518.5 mmol) of concentrated sulphuric acid are slowly added dropwise while cooling with ice. This solution is cooled to 5° C. and slowly added dropwise to 30 ml (232 mmol) indane cooled to 0-5° C., with vigorous stirring and further cooling with ice. The reaction mixture is stirred for 30 min at 0-5° C., and then heated to 25° C. for 1 h with stirring. Then the solution is added dropwise to 150 ml ice/water and stirred for 30 min. The aqueous phase is extracted three times with 200 ml diethyl ether. The combined organic phases are washed twice with 200 ml saturated sodium hydrogen carbonate solution and once with 150 ml distilled water. Then the organic phase is dried with MgSO4 and the solvent is eliminated in vacuo. The crude product is dissolved in 250 ml of methanol and combined with 4.5 g Raney nickel. The reaction mixture is hydrogenated for 16 h at 3 bar H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (75:25).
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[C:7]([CH2:16][NH2:17])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)([O-])=O>[Pd].CCO.CO>[NH2:17][CH2:16][C:7]1[C:6]([NH2:3])=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: NCc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: NCc1ccc2cccnc2c1N
Reaction time: 5 h
Yield: 2.6 %

Procedure:
Palladium on Carbon (5%, 25 mg) was added to a solution of C-(8-nitroquinolin-7-yl)-methylamine dihydrochloride (Intermediate 210) (180 mg, 1.09 mmol) in EtOH (10 ml) and the mixture was stirred under an atmosphere of hydrogen for 5 h. The mixture was diluted with MeOH (10 ml), filtered through celite and the filtrate was concentrated in vacuo to give the title compound (5 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[CH3:23][N:24]([CH3:31])[CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][NH2:28]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][N:24]([CH3:31])[CH3:23])=[O:6]
Reactant: CN(C)CC(C)(C)CN
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(C)(C)CNC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 2.2 g, 10.00 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (2.095 mL, 12.00 mmol) added. The mixture was cooled in an ice/water bath and N,N,2,2-tetramethyl-1,3-propanediamine (3.652 mL, 10.00 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was washed with brine, 2N NaOH (aq.), dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeOH/DCM) gave the title compound as a yellow oil 17171/2/1 (2.29 g, 77%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([O:30][CH2:31][CH3:32])=[CH:25][N:24]=1)([O-])=O>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]2[NH:28][C:27](=[O:29])[C:26]([O:30][CH2:31][CH3:32])=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cnc(N[N+](=O)[O-])[nH]c1=O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Product: CCOc1cnc(NCCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (1.64 g), 2-nitroamino-5-ethoxypyrimidin-4-one (1.2 g) and pyridine (15 ml) were stirred under reflux conditions for 18 hours. Pyridine was evaporated under reduced pressure and water (25 ml) and chloroform (25 ml) added. The mixture was shaken, the chloroform layer extracted; the aqueous layer was further extracted with chloroform (2×25 ml), and the combined chloroform extracts were washed with water, dried (MgS04) and evaporated under reduced pressure. The resultant residue was subjected to column chromatography on silica gel using chloroform: methanol (95:5) as eluant. The desired fractions were evaporated to give the title product as a residue. This residue was washed with diethyl ether and dissolved in isopropanol. This solution was treated with maleic acid (0.77 g) in isopropanol to give a solid maleate salt which on crystallisation from ethanol gave 2-[3-[3-(piperidinomethyl)phenoxy]propylamino ]-5-ethoxypyrimidin-4-one dimaleate (1.11 g), m.p. 68°-71° C.
Reaction SMILES: [OH:1][CH:2]([CH2:15][N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:1][C@@H:2]([CH2:15][N:16]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=c1[nH]c2cccc(OCC(O)CN(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=c1[nH]c2cccc(OC[C@@H](O)CN(Cc3ccccc3)Cc3ccccc3)c2[nH]1

Procedure:
4-[2-Hydroxy-3-(N,N dibenzylamino)propoxy]-1,3-dihydro-2H-benzimidazol-2-one (4.35 g, 10.8 mmol) was dissolved in methanol (200 mL) and treated with a vast excess of ammonium formate (13.0 g, 0.21 mol), followed by 10% palladium on carbon (1.5 g). The suspension was stirred at reflux for 3 hours. After cooling the suspension, the reaction mixture was filtered through Celite. The filtrate concentrated in vacuo to a pale brown oil which slowly crystallized upon standing. The resulting solid was triturated using chloroform containing methanol and filtered to give 1.56 g (65%) as the desired product of a pale grey solid. NMR. MS.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].[B-]C#N.[Na+].C(O)(=O)C>CO>[CH2:11]([N:13]([CH2:14][CH3:15])[CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH3:12]
Reactant: CCNCC
Reactant: O=C1Cc2ccccc2C1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)C1Cc2ccccc2C1
Reaction time: 8 h

Procedure:
To a solution of 1H-inden-2(3H)-one (6.00 g, 45.4 mmol) in methanol (100 ml) was added diethylamine (6.64 g, 91 mmol), sodium cyanotrihydroborate (5.71 g, 91 mmol) and acetic acid (5.45 g, 91 mmol). The reaction mixture was stirred overnight and concentrated. The residue was diluted with methylene chloride, washed with saturated aqueous NaHCO3 (2×50 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was dissolved in 1M aqueous HCl (100 ml), and extracted with methylene chloride (2×50 mL). The aqueous layer was treated with 6N aqueous NaOH solution until the pH=14 and was extracted with methylene chloride (4×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide the title compound.