Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C[O-].[Na+].[C:22](OCC)(=O)[CH3:23]>CO>[CH3:22][C:23]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1
Reactant: CCOC(C)=O
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 87 %

Procedure:
5.04 g. of 2-(theophyllin-7-yl)-acetamidoxime, 2.16 g. of sodium methylate and 10 cm3 ethyl acetate are heated under shaking and under pressure in 150 cm3 methanol at 100° C. for 8.5 hours. After processing 4.8 g. (87% yield) of 7-[(5-methyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are obtained. M.p.: 135°-136° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][N:6]=1.[CH3:9][NH2:10]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:10][CH3:9])=[CH:5][N:6]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: CN
Solvent: CCO
Product: CNCc1cnc(Cl)s1
Temperature: 20 °C

Procedure:
2-Chloro-5-thiazolylmethylchloride (5.0 g, 0.03 mol) and methylamine (4.6 g, 0.15 mol) were dissolved in ethanol (50 ml). The resulting solution was heated under reflux for 2 hours. The resulting mixture was allowed to cool to ambient temperature (20° C.) and the solvent was removed by evaporation under reduced pressure. The residue was added to a mixture of dichloromethane (150 ml) and aqueous sodium hydroxide (2N, 50 ml) and the mixture agitated. The two phases were allowed to separate and the aqueous phase was removed. Further aqueous sodium hydroxide (2N, 50 ml) was added to the organic phase and the step repeated. The aqueous phases were combined and washed with dichloromethane (50 ml). The dichloromethane product so obtained was combined with the original organic phase, washed with saturated brine (100 ml) and dried using magnesium sulphate. The solvent was evaporated to give N-(2-chloro-5-thiazolylmethyl)-N-methylamine as a yellow oil in a yield of 3.55 g (73%).
Reaction SMILES: C(=O)C1C=CC=CC=1.S1CC(=O)NC1=O.[CH:16](=[C:23]1[S:27][C:26](=[O:28])[NH:25][C:24]1=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.[Pd]>[CH2:16]([CH:23]1[S:27][C:26](=[O:28])[NH:25][C:24]1=[O:29])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1NC(=O)C(=Cc2ccccc2)S1
Agent: [Pd]
Agent: O=C1CSC(=O)N1
Solvent: C1COCCO1
Solvent: O=Cc1ccccc1
Product: O=C1NC(=O)C(Cc2ccccc2)S1

Procedure:
Benzaldehyde (10.6 g) and 2,4-thiazolidinedione (11.7 g) were reacted together by a procedure analogous to that described in Example 1. The resulting material, 5-benzylidene-2,4-thiazolidinedione (18.5 g) was dissolved in dioxan (300 ml) and hydrogenated over 10% Palladium-charcoal (18.5 g) at 200 psi, overnight. The mixture was filtered through diatomaceous earth, the filter cake thoroughly washed with dioxan, and the combined dioxan solutions evaporated to afford the title compound, mp 83°-86° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3Br)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][B-](F)(F)F)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCCC1.O.CC(O)=O.CC(O)=O.[Pd].C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:45][N:42]2[CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40][CH2:41]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(NC(=O)c2cc3cccc(Br)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCN(C[B-](F)(F)F)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
8.99 g 7-bromo-1-methyl-1H-indole-2-carboxylic acid-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide and 5.95 g potassium ((4-(tert.-butoxycarbonyl)-piperazin-1-yl)-methyl)-trifluoroborate (for preparation see Org. Lett. 2007, 9, 1597-1600) are dissolved in 150 ml of tetrahydrofuran and 15 ml of water, combined with 17.3 g caesium carbonate and argon is piped through the resulting solution for 10 minutes. Then 120 mg palladium-II-acetate and 1.23 g 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (XPhos) are added and the mixture is heated to 80° C. for 12 hours. Then it is divided between water and ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo. The crude product is further reacted directly.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:20]1[CH:24]=[CH:23][N:22]=[N:21]1)[CH2:17][C:18]#[CH:19].C(NC(C)C)(C)C.C(OCC)(=O)C>C1COCC1.[Cu](I)I>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]#[C:18][CH2:17][CH2:16][N:20]2[CH:24]=[CH:23][N:22]=[N:21]2)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCn1ccnn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cn1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(C#CCCn2ccnn2)cn1
Yield: 69.6 %

Procedure:
(5-Iodo-pyridin-2-yl)-carbamic acid tert-butyl ester (3.45 g, 10.77 mmol) was dissolved in anhydrous THF (30 ml) under an argon atmosphere and treated with (PPh3)2Pd(II)Cl2 (0.6 g, 0.86 mmol) and copper iodide (0.2 g, 1.1 mmol). To this mixture a solution of 1-but-3-inyl-1H-[1,2,3]triazole (2.1 g, 17.24 mmol) in anhydrous THF (20 ml) is added dropwise at 0° C. followed by diisopropyl-amine (7.6 mL, 53.88 mmol). After stirring for 6 h at room temperature ethyl acetate (100 mL) was added, the mixture was washed with water, brine and dried over sodium sulfate. After removal of the solvents the crude product was purified by column chromatography on silica gel (dichloro methane/methanol 98:2) yielding [5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyridin-2-yl]-carbamic acid tert-butyl ester as light yellow solid (2.35 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:34](=[O:36])[CH3:35])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(NC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Yield: 50.4 %

Procedure:
To a mixture of crude 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (200 mg) and triethylamine (0.130 mL, 0.933 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (0.0530 mL, 0.561 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min, diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-90% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (111 mg, 0.246 mmol).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[C:21](Br)[CH:20]=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[C:27]([Zn]C#N)#[N:28]>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:26])([F:25])[C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: N#C[Zn]C#N
Reactant: CC(C)(NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(NC(=O)c1nn(-c2cc(C#N)ccn2)c2c1C[C@H]1C[C@@H]21)C(F)(F)F
Temperature: 130 °C
Yield: 42.2 %

Procedure:
To a mixture of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide (35 mg, 0.082 mmol) and dicyanozinc (19.2 mg, 0.164 mmol) in DMA (2 mL) under nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (9.4 mg, 0.0081 mmol) was added. The reaction was heated in a heavy-walled sealed tube under microwave irradiation at 130° C. for 1 h. The mixture was purified by preparative HPLC to give the title compound (13 mg). LCMS m/z=376.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.44-0.47 (m, 1H), 1.26 (td, J=7.9 and 4.9 Hz, 1H), 1.72 (s, 6H), 2.25-2.32 (m, 1H), 2.76-2.82 (m, 1H), 2.92 (d, J=16.9 Hz, 1H), 3.00 (dd, J=16.7 and 6.2 Hz, 1H), 6.87 (bs, 1H), 7.42 (dd, J=5.0 and 1.4 Hz, 1H), 8.15 (s, 1H), 8.62 (d, J=5.0 Hz, 1H).
Reaction SMILES: [CH3:1]N(C)C1NC(=O)C(CCO)=C(C)N=1.[Cl:15][CH2:16][CH2:17][C:18]1[C:19](=[O:29])[N:20]([CH3:28])[C:21]([N:25](C)[CH3:26])=[N:22][C:23]=1[CH3:24].ClCCC1C(=O)N(CCC)C(N(C)C)=NC=1C.Cl.ClCCC1C(=O)N(CC)C(N(C)C)=NC=1C>>[Cl:15][CH2:16][CH2:17][C:18]1[C:19](=[O:29])[N:20]([CH3:28])[C:21]([NH:25][CH2:26][CH3:1])=[N:22][C:23]=1[CH3:24]
Reactant: Cc1nc(N(C)C)[nH]c(=O)c1CCO
Reactant: Cc1nc(N(C)C)n(C)c(=O)c1CCCl
Agent: CCCn1c(N(C)C)nc(C)c(CCCl)c1=O
Agent: CCn1c(N(C)C)nc(C)c(CCCl)c1=O
Agent: Cl
Product: CCNc1nc(C)c(CCCl)c(=O)n1C

Procedure:
and further, following the same procedures 2-dimethylamino-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone (Coll. Czech. Chem. Commun., 32, 1582, 1967) was converted into 5-(2-chloroethyl)-2-(dimethylamino)-3,6-dimethyl-4(3H)-pyrimidinone (interm. 32); 5-(2-chloroethyl)-2-(dimethylamino)-6-methyl-3-propyl-4(3H)-pyrimidinone (interm. 33); and 5-(2-chloroethyl)-2-(dimethylamino)-3-ethyl-6-methyl-4(3H)-pyrimidinone monohydrochloride (interm. 34).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[NH:5][N:4]=1.C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>O>[C:8]([C:6]1[NH:5][N:4]=[C:3]([N:2]([CH3:1])[C:18](=[O:19])[O:20][CH3:21])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)Cl
Reactant: CNc1cc(C(C)(C)C)[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)N(C)c1cc(C(C)(C)C)[nH]n1
Yield: 64.2 %

Procedure:
70 g of 3-(N-methylamino)-5-t-butylpyrazole as prepared in Reference Example was dissolved in 1.5 l of water together with 46 g of sodium bicarbonate, and 52 g of methyl chloroformate was added dropwise to the aqueous solution over 1.5 hours at 10° C. The mixture was allowed to react at 10° C. for 1 hour. After completion of the reaction, the solid product was collected by filtration, washed with water and hexane and dried to obtain 62 g of methyl N-(5-tert-butyl-3-pyrazolyl)-N-methylcarbamate.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[CH:6][CH:5]=1)#[N:3].C(N(CC)CC)C.Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([S:28]([CH:27]=[CH2:26])(=[O:30])=[O:29])[CH2:11][C:10]2=[O:15])=[CH:16][CH:17]=1)#[N:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: N#Cc1ccc(CN2CCNCC2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCN(Cc2ccc(C#N)cc2)C(=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
To a solution of 1-(4-cyanobenzyl)-2-piperazinone hydrochloride (3.85 g) and triethylamine (12.5 ml) in dichloromethane (50 ml) was added dropwise a solution of 2-chloroethanesulfonyl chloride (4.08 g) in dichloromethane (10 ml) at 0° C., and the mixture was stirred at 0° C. for 4 hours. The reaction solution was diluted with dichloromethane, washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of 1-(4-cyanobenzyl)-4-vinylsulfonyl-2-piperazinone (3.15 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[C:29]([O:33][C:34](=[O:45])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][NH2:44])[CH:38]=1)([CH3:32])([CH3:31])[CH3:30]>C1COCC1.CCOC(C)=O>[C:29]([O:33][C:34](=[O:45])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][NH:44][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[CH:38]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (0.5 g, 2.25 mmol) in THF (25 mL) is added carbonyl diimidazole (0.5 g, 2.7 mmol) and heated at 60° C. for 2 hours. The mixture is cooled to room temperature and (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (0.67 mL, 2.7 mmol) is added. The mixture is stirred for 12 h, diluted with EtOAc (100 mL), washed with brine (2×50 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford [3-({[2-(3-fluoro-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (0.8 g, 80%) as a solid. MS: 437 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.35 (s, 9H), 4.13 (d, J=6.1 Hz, 2H), 4.54 (d, J=5.9 Hz, 2H), 7.27-7.48 (m, 4H), 7.62 (m, 1H), 8.16 (m, 1H), 8.31 (m, 1H), 9.32 (s, 2H), 9.43 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16]1[C:29]2[CH:28]=[C:27]([NH2:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:13]1[C:14]2[CH:15]=[C:2]([NH:30][C:27]3[C:26]4[C:21]([C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:29]=5[CH:28]=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cc2ccccc2c2ccccc12
Reactant: Brc1cc2ccccc2c2ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)cc(Nc1cc3ccccc3c3ccccc13)c1ccccc12
Reaction time: 12 h
Yield: 45 %

Procedure:
9-bromophenanthrene (7.00 g, 27.22 mmol), phenanthren-9-amine (5.26 g, 27.22 mmol), Pd2(dba)3 (499 mg, 0.544 mmol), tris-t-butylphosphine (0.123 mL, 0.544 mmol), sodium tert-butoxide (3.90 mg, 40.84 mmol) were put in a 250 mL two-neck flask and dissolved in toluene. The solution was refluxed and stirred for 12 hours. After completion of the reaction, the solution was extracted with DI water/methylenechloride and distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of n-hexane and methylenechloride (3:1) and was re-crystallized in a solution of methylene chloride and petroleum ether such that the solid compound was obtained, (4.50 g, yield: 45%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][C:15]1[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=1)[CH:8]=2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.CCOC(C)=O>C1COCC1>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([CH2:3][OH:2])[NH:6]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(Oc3nc4ccccc4s3)cc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cc2ccc(Oc3nc4ccccc4s3)cc2[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a cooled (−78° C.) solution of 6-(benzothiazol-2-yloxy)-1H-indole-2-carboxylic acid methyl ester (200 mg, 0.61 mmol) in THF (6 mL) was added LAH (2 M in THF, 0.34 mL, 0.31 g, 0.68 mmol) and the reaction mixture was stirred (−78° C., 1 h). The reaction mixture was treated with H2O (5 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×25 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH (0.2 M NH3):DCM (0-4%) to provide the title compound as a beige solid (97 mg, 53%). MS (ESI): mass calcd. for C16H12N2O2S, 296.1; m/z found, 297.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.63 (s, 1H), 7.72 (d, J=8.1, 1H), 7.64 (dd, J=8.0, 0.7, 1H), 7.57 (d, J=8.5, 1H), 7.41-7.31 (m, 2H), 7.27-7.21 (m, 1H), 7.07 (dd, J=8.5, 2.2, 1H), 6.39 (s, 1H), 4.80 (d, J=5.9, 2H), 1.87 (t, J=5.9, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[N:32]=[CH:33][S:34][C:35]=1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:35]4[S:34][CH:33]=[N:32][C:31]=4[CH3:30])=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ncsc1C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2scnc2C)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 4-methylthiazole-5-carboxylic acid (21 mg, 0.15 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1.[N:21]([C:24]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26](OC)=[O:27])=[C:22]=[S:23]>O1CCCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]3[C:26](=[O:27])[C:25]4[C:24](=[CH:33][C:32]([N+:34]([O-:36])=[O:35])=[CH:31][CH:30]=4)[NH:21][C:22]3=[S:23])[CH2:11][CH2:10]2)=[O:13])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N=C=S
Reactant: NCCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=S)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a stirred solution of 28 parts of [1-(4-aminobutyl)-4-piperidinyl](4-fluorophenyl)methanone in 135 parts of tetrahydrofuran was added dropwise during a 10 minutes-period a solution of 24 parts of methyl 2-isothiocyanato-4-nitrobenzoate in 180 parts of tetrahydrofuran (slightly exothermic reaction). Upon completion, stirring was continued overnight at room temperature. The solid was filtered off and crystallized from ethanol while stirring and cooling to 40° C. The product was filtered off, washed with ethanol and dried in vacuo at 80° C., yielding 30 parts (62%) of 3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl]-2,3-dihydro-7-nitro-2-thioxo-4(1H)-quinazolinone; mp. 225° C. (20).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[C:10]1([CH3:20])[CH:15]=CC(S(O)(=O)=O)=C[CH:11]=1>C(O)(C)(C)C>[C:10]([O:8][C:7]([CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)=[O:9])([CH3:20])([CH3:15])[CH3:11]
Reactant: O=C(O)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C1CCNCC1
Temperature: 25 °C

Procedure:
12.9 g of 4-piperidine carboxylic acid is completely dissolved in 35 ml of t-butyl alcohol (R1OH) and refluxed for 10 hrs. in the presence of 3.8 g of para-toluene sulfonic acid. After being cooled to room temperature, the resulting reaction is washed three times with 20 ml of saturated NaHCO3 and then, once with 25 ml of brine water and dried over MgSO4 to give piperidine-4-carboxylic acid t-butyl ester.
Reaction SMILES: CS[S:3][CH3:4].Br[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[CH:9]=[O:10]>N1C=CC(C)=CC=1C.[Cu]>[CH3:19][O:18][C:12]1[CH:11]=[C:8]([CH:7]=[C:6]([S:3][CH3:4])[C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[CH:9]=[O:10]
Reactant: CCCOc1c(Br)cc(C=O)cc1OC
Reactant: CSSC
Agent: [Cu]
Solvent: Cc1ccnc(C)c1
Product: CCCOc1c(OC)cc(C=O)cc1SC
Temperature: 25 °C
Yield: 12.6 %

Procedure:
50 ml (0.56 mole) of methyl disulfide in 400 ml of 2.4-lutidine was added 46 g (0.72 mole) of copper. The mixture was heated at 140° for 3 hours. The solution was cooled to room temperature and 74.90 g (0.56 mole) of 3-bromo-5-methoxy-4-propoxybenzaldehyde was then added. The mixture was refluxed for 16 hours at 175° C. The solution was filtered and the filtrate was concentrated to dryness. The product was purified by flash column chromatography first then recrystallized from hexane to give 17.01 g (26% yield) of 3-methoxy-5-methylthio-4-propoxybenzaldehyde as a white solid. m.p. 64°-66° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C@H:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C@H:18]([CH3:20])[NH2:19])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>ClCCl>[CH3:20][C@H:18]([NH:19][C:39]([C:35]1[O:34][CH:38]=[CH:37][CH:36]=1)=[O:40])[C@@H:17]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[N:8]=[CH:9]2
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccncc2)c1)c1ccccc1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccco1)[C@H](Oc1ccc2c(cnn2-c2ccncc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
(αS,βR)-β{[1-(4-Pyridyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (64.3 mg, 0.19 mmol) is dissolved in 7.1 mL of dichloromethane. Triethylamine (0.062 mL, 0.45 mmol) and 2-furoylchloride (24.3 mg, 0.19 mmol) are added. After 4 h stirring at r.t. the reaction mixture is diluted with dichloromethane, washed with water and brine and dried over Na2SO4. The reaction mixture is filtered, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane). 53.7 mg (65.6%) of the title compound are obtained.