Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=2[F:29])=[N:10]1.C1C(=O)N([Br:37])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:37])[NH:12][C:11]([C:21]2[C:22]([F:29])=[CH:23][C:24]([F:28])=[CH:25][C:26]=2[F:27])=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Yield: 55.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(2,4,6-trifluorophenyl)-1,4-dihydropyrimidine-5-carboxylate (6.31 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in CN200610098646.3) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (4.1 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([N:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[N:9]2)=[C:4]([C:25]([N:27]2[C@H:36]([CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)=[O:26])[CH:3]=1.CCN(CC)CC.[C:53]1([S:59](Cl)(=[O:61])=[O:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(Cl)Cl.O>[CH2:17]([N:16]([CH2:21][CH2:22][CH2:23][CH3:24])[C:14]([C:10]1[CH:11]=[C:12]([CH3:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:59]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)(=[O:61])=[O:60])=[CH:3][C:4]=2[C:25]([N:27]2[C@H:36]([CH2:37][O:38][Si:39]([C:42]([CH3:43])([CH3:45])[CH3:44])([CH3:41])[CH3:40])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)=[O:26])[N:9]=1)=[O:15])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(N)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(NS(=O)(=O)c3ccccc3)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a ice-cooled solution of (S)-1-(4-amino-2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-5-methyl-1H-pyrazole-3-carboxamide (intermediate B, 0.20 g, 0.316 mmol) in DCM (2 mL) was added Et3N (0.05 mL, 0.47 mmol) and benzenesulfonyl chloride (0.06 g, 0.38 mmol) followed by stirring at RT for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford (S)—N,N-dibutyl-1-(2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(phenylsulfonamido)phenyl)-5-methyl-1H-pyrazole-3-carboxamide as a mixture of mono and bis sulfonamides, 0.21 g (crude). The crude reaction mass was used in the next reaction without further purification. Rf=0.75 (50% EtOAc in hexane); ES-MS: m/z 772.6 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][C:3]=1[CH3:19].[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].O>CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[CH3:19])[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25]
Reactant: CC(C)(C)S(N)=O
Reactant: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Yield: 44.6 %

Procedure:
6′-Bromo-4-methoxy-5′-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 4, 1.38 g, 4.27 mmol) and 2-methylpropane-2-sulfinamide (0.931 g, 7.68 mmol) were dissolved in 2-Me THF (8 mL). Titanium(IV) ethoxide (1.78 mL, 8.53 mmol) was added and the resulting mixture was heated to reflux overnight. 2-Methylpropane-2-sulfinamide (0.259 g, 2.13 mmol) and titanium(IV) ethoxide (0.624 mL, 2.99 mmol) were added and heating was continued. After a total of 4 days, the reaction was allowed to cool to r.t. and diluted with EtOAc (25 mL). Water (12 mL) was added dropwise under vigorous stirring and after stirring for another 10 min, the mixture was allowed to stand without stirring for 1.5 h. The solids were filtered off and the solvent was evaporated. The residue was purified by flash chromatography using a gradient of 0-30% EtOAc in heptane as eluent to afford 812 mg (45% yield) of the title compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23 (m, 9 H), 1.31 (m, 2 H), 1.58 (m, 4 H), 1.90 (m, 1 H), 2.02 (m, 1 H), 2.42 (s, 3 H), 2.98 (m, 2 H), 3.18 (m, 1 H), 3.25 (m, 3 H), 7.51 (m, 1 H), 8.53 (m, 1 H); MS (ES+) m/z 426, 428 [M+H]+.
Reaction SMILES: NCCCN.[CH2:6]([OH:14])[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]>CCCCCC>[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13]
Reactant: CCCCC#CCCO
Agent: NCCCN
Solvent: CCCCCC
Product: C#CCCCCCCO
Temperature: 25 °C

Procedure:
35% KH in mineral oil (27 g, 240 mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0° C. and 3-octyn-1-ol (10 g, 79 mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50 mL) and the product was extracted into ether. The organic layer was washed with 10% HCl and brine and dried (MgSO4). Evaporation gave a colorless oil which was used without further purification: 1H NMR (90 MHz, CDCl3) δ3.65 (t, J=5 Hz, 2H, O--CH2), 2.23 (m, 2H, CH2), 2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) nmax 3350, 2930, 2125 cm-1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22]([CH2:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+]>>[NH:36]1[C:19]([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:21]=[C:22]([CH2:24][CH2:25][C:26]5[CH:35]=[CH:34][C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=5)[N:23]=[C:8]4[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)=[N:20][N:38]=[N:37]1
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: c1ccc2nc(CCc3cn4c(-c5ccc(-c6nnn[nH]6)nc5)cnc(N5CCOCC5)c4n3)ccc2c1
Yield: 10 %

Procedure:
Compound 3b (300 mg, 0.650 mmol) was treated with NaN3 as described in Example 1, Step H to obtain the title compound 77 as a light yellow solid (37.2 mg, 10% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.79 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.04-8.02 (m, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 7.70 (t, J=7.2 Hz, 1H), 7.56-7.46 (m, 3H), 4.21-4.09 (m, 4H), 3.75-3.65 (m, 4H), 3.35-3.25 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H24N10O: 505.2 (M+H). Found 505.3.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33](C)[C:34](=O)OC(C)(C)C)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][NH:33][CH3:34])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a stirred solution of tert-butyl 3-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)propyl(methyl)carbamate (0.1 g, 142 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo. 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane was added. After 1 h, the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-[5-difluoromethoxy-1-(3-methylamino-propyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (53 mg, 78%). MS (M+H)+=472; 1H NMR (DMSO-d6) δ: 9.30 (s, 1H), 8.61 (s, 1H), 8.43 (s, 1H), 8.08-8.14 (m, 2H), 7.59-7.68 (m, 1H), 7.12-7.71 (m, 1H), 4.82 (t, J=6.7 Hz, 4H), 3.54 (br. s., 3H), 2.27 (t, J=6.8 Hz, 2H), 1.73 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18](I)=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1C=CC=C[CH:27]=1.NC1C=CC(CN/C=C2\C(=O)NC(=O)C3C\2=CC([Br:51])=CC=3)=CC=1O[Si](C(C)C)(C(C)C)C(C)C.C(Cl)(=O)C=C>>[Br:51][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:22])[NH:13][C:12](=[O:23])/[C:11]/2=[CH:10]\[NH:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([NH:24][C:25](=[O:32])[CH:26]=[CH2:27])=[C:2]([OH:1])[CH:7]=1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(NC(=O)c2ccccc2)c(O)c1
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)ccc1N)(C(C)C)C(C)C
Agent: C=CC(=O)Cl
Product: C=CC(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]benzamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}-amino)methylene]-6-bromoisoquinoline-1,3(2H,4H)-dione (54 mg, 0.10 mmol) is reacted with acryloyl chloride (41 μL, 0.50 mmol). Following desilylation, precipitation, and washing with methanol and diethyl ether, N-[4-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2-hydroxyphenyl]acrylamide is obtained (8 mg, 18
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH3:31])[CH2:24][CH2:23]3)[CH:18]=2)[N:13]=[CH:12]1.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1>>[CH3:31][O:30][CH2:29][CH2:28][N:25]1[CH2:26][CH2:27][N:22]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][N:11]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=2[CH3:1])[C:6]([NH:32][C:33]2[CH:37]=[CH:36][O:35][N:34]=2)=[O:7])[C:20]3=[O:21])[CH2:23][CH2:24]1
Reactant: Nc1ccon1
Reactant: COCCN1CCN(c2ccc3ncn(-c4cc(C(=O)O)ccc4C)c(=O)c3c2)CC1
Product: COCCN1CCN(c2ccc3ncn(-c4cc(C(=O)Nc5ccon5)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 4-methyl-3-[6-(4-(2-methoxyethyl)piperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid was reacted with 3-aminoisoxazole to give 3-[6-(4-(2-methoxyethyl)piperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 2.58 (m, 6H), 3.26 (m, 7H), 3.47 (t, 2H), 7.05 (s, 1H), 7.50 (s, 1H), 7.66 (m, 3H), 8.10 (m, 2H), 8.13 (s, 1H), 8.87 (s, 1H), 11.48 (s, 1H); Mass Spectrum: M+H+ 489.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=N[CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C@@H:18]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=2)[CH3:19])[CH:15]=[CH:16][CH:17]=1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.Cl>ClCCCl>[Cl:27][C:23]1[N:22]=[C:21]([NH:20][C@H:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][CH:5]([C:4]3[CH:8]=[CH:9][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH3:28])[CH:13]=2)[CH3:19])[CH:26]=[N:25][CH:24]=1
Reactant: CC(=O)c1cncc(C)c1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cccc(C(C)Nc2cccc([C@H](C)Nc3cncc(Cl)n3)c2)c1
Temperature: 80 °C
Yield: 14.2 %

Procedure:
To a solution of 1-(5-methylpyridin-3-yl)ethanone (135 mg, 1 mmol) and N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (248 mg, 1 mmol) in 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (300 mg, 1.4 mmol), in one portion, and glacial acetic acid (0.18 mL, 3 mmol). The mixture was heated in the microwave reactor at 80° C. for 1 hour. After this time the mixture was stirred with dilute aqueous hydrochloric acid (2M, 7 mL) for 15 minutes and the two phases were separated. The aqueous phase was basified to pH 9 with solid potassium hydroxide and was extracted with dichloromethane (2×20 mL). The extracts were washed with brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give an orange oil which was purified by flash chromatography (silica, ethyl acetate/methanol) to give 6-chloro-N-[(1S)-1-(3-{[1-(3-methylphenyl)ethyl]amino}phenyl)ethyl]pyrazin-2-amine (52 mg, 14%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8](=O)([O-])O.[Na+].[N+:13]([C:16]1[CH:26]=[CH:25][C:19]([CH2:20][O:21][C:22](Cl)=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>O.C(OCC)C>[OH:4][CH2:3][C@H:2]([NH:1][C:22]([O:21][CH2:20][C:19]1[CH:25]=[CH:26][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1)=[O:23])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])O
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)[C@H](CO)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 24.2 %

Procedure:
To a stirred solution of L-serine (3.5 g) and sodium hydrogen carbonate (7.5 g) in water (46 ml) was added 4-nitrobenzyloxycarbonyl chloride (6.4 g) in diethyl ether (10 ml) at ambient temperature. After stirring for 2 hours, to the solution were added 4-nitrobenzyloxycarbonyl chloride (6.4 g) in diethyl ether (10 ml), and sodium hydrogen carbonate (3.6 g). After stirring for 3 hours, the aqueous layer was separated and washed with ethyl acetate After adjusting the pH to 2 with concentrated hydrochloric acid, the aqueous solution was extracted twice with ethyl acetate, dried over magnesium sulfate and evaporated. To the residue were added methanol (40 ml) and concentrated sulfuric acid (0.7 ml), and the solution was stirred at 50°-55° C. for 2.5 hours. To the mixture was added triethylamine (4.2 ml) and the mixture was evaporated in vacuo. The resulting residue was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed twice with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (300 ml) and eluted with a mixture of acetone and dichloromethane (8:92, V/V) to give methyl (2S)-3-hydroxy-2-[(4-nitrobenzyloxycarbonyl)amino]propionate (2.14 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.Cl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[OH:32][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:3][CH:4]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=2[O:11][CH2:10][CH:9]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1
Reactant: ClCCN1CCCCC1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Yield: 7 %

Procedure:
4-(4-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (310 mg, 0.59 mmol) prepared in Example 15, [1-(2-chloroethyl)]piperidine.HCl (176 mg, 0.9 mmol) and K2CO3 (264 mg, 1.8 mmol) were dissolved in acetone (8 ml) and then refluxed for 62 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer thus separated was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The residue was separated by column chromatography (n-hexane:ethyl acetate=1:2) to obtain 83 mg (yield: 7%) of the title compound as a white foam.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1nccc2cnccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2cnccc12

Procedure:
1-Hydroxy-2,6-naphthyridine (550 mg) [prepared according to the method of Sakamoto, T. et al Chem. Pharm. Bull. 33, 626, (1985)] was stirred with phosphorous oxychloride (10 ml) at 110° for 5 h. The volatiles were removed in vacuo and the residue treated carefully with ice. After diluting with water (to ˜25 ml), solid NaHCO3 was added to effect neutralisation and the product extracted into EtOAc (2×80 ml). The combined organic extracts were dried (MgSO4), evaporated in vacuo, and the crude product chromatographed (SiO2; EtOAc) affording the title compound as a slightly yellow solid (420 mg, 68%). δH (CDCl3) 9.35 (1H, s), 8.82 (1H, d, J 5.9 Hz), 8.48 (1H, d, J 5.6 Hz), 8.00 (1H, d, J 5.9 Hz), 7.74 (1H, d, J 5.6 Hz); m/z (ES+, 70V) 165 and 167 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CC(O)C.C([O-])(O)=O.[Na+]>[CH3:9][N:8]([CH:10]1[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:11]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccncc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccncc2)C1
Yield: 61 %

Procedure:
3-(N-Tert-butoxycarbonyl-N-methylamino)pyrrolidine (4.993 mmol, 1 eq) and 4-chloropyridine hydrochloride (14.979 mmol, 3 eq) were dissolved in 2-propanol (15 ml) and DIPEA (19.972 mmol, 4 eq) and refluxed for 16 h. After monitoring by thin-layer chromatography, the reaction solution was diluted with sat. NaHCO3 solution and extracted with ethyl acetate (3×20 ml). The combined org. phases were washed with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia (25% aq)). Yield: 61%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]([CH3:9])[CH3:8].C([Li])CCC.[CH3:18][S:19]SC.O>C1COCC1.C(OCC)C>[CH3:18][S:19][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:5]=1[CH2:6][N:7]([CH3:9])[CH3:8]
Reactant: CSSC
Reactant: COc1cccc(CN(C)C)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(CN(C)C)c1SC
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
Under a nitrogen atmosphere, 3-methoxy-N,N-dimethylbenzylamine (2.00 g, 12.1 mmol) was dissolved in anhydrous THF (20 mL) and cooled to 0° C. in an ice bath. 2.5M n-butyl lithium in hexanes (5.3 mL, 13.3 mmol) was added slowly, maintaining the temperature to below 5° C. The reaction was stirred at 0° C. for 2 h, then dimethyldisulfide (1.59 g, 13 mmol) was slowly added over 90 min, maintaining the temperature to below 5° C. The reaction mixture was stirred for 17 h, during which time the temperature was allowed to reach room temperature. Water (20 mL) and diethyl ether (30 mL) were added and the organic layer was separated and dried with MgSO4. After filtration, the crude solution was dissolved in ethyl acetate and absorbed in vacuo onto silica gel (1.5 g). This material was chromatographed on an ISCO CombiFlash Chromatography System to yield (2-methylsulfanyl-3-methoxybenzyl)-dimethyl-amine as a yellow oil (1.47 g, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[C:20]([Cl:26])=[N:21][CH:22]=[N:23][C:24]=1Cl)([O-:18])=[O:17]>O1CCCC1.C(OCC)(=O)C>[Cl:26][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=2)[C:19]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: Nc1ccnc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(Cl)ncnc1Nc1ccnc(Cl)c1
Yield: 18.7 %

Procedure:
4-Amino-2-chloropyridine (8.0 g, 62.2 mmol) and triethylamine (8.7 mL) were added. successively to a suspension of 5-nitro-4,6-dichloropyrimidine (8.0 g, 41.2 mmol) in tetrahydrofuran (160 mL), and the mixture was heated under reflux for 4 hours. After cooling as it was, the reaction solution was diluted with ethyl acetate (160 ml) and washed with 160 ml water and brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue were suspended in diethyl ether, and the resulting solid was collected by filtration and air-dried, to give the title compound (2.2 g, 19%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][C@H:15]1[O:20][C@:16]1([CH3:19])[CH2:17][OH:18].[H][H]>CO.O.[Ni]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:19])([OH:20])[CH2:17][OH:18]
Reactant: [H][H]
Reactant: COc1c(C)c(C)c(OC)c(C[C@H]2O[C@]2(C)CO)c1C
Agent: [Ni]
Solvent: O
Solvent: CO
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Yield: 86.4 %

Procedure:
185 mg of (2R,3R)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-2-methylbutanol are dissolved in 5 ml of methanol and the solution is subsequently diluted with 5 ml of water. Thereupon, Raney-nickel is added and the mixture is heated at reflux under hydrogen for 2 hours. After the hydrogen uptake has finished the mixture is filtered, the filter residue is washed with methanol and methylene chloride and the combined filtrate and washings are concentrated on a rotary evaporator. Residual water is distilled off azeotropically by the addition of methylene chloride. The oil obtained is recrystallized from n-hexane/diethyl ether and there are obtained 161 mg of 55% (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-butanediol (48% yield; GC analysis of the acetonide). Data of the pure substance: M.p. 86°-87° C.; [α]D20 +2.55° (c=5.3% in CHCl3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.Cl.[OH:20][CH2:21][C:22]1([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(OCCO)C.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([N:25]2[CH2:26][CH2:27][C:22]([CH2:21][OH:20])([OH:28])[CH2:23][CH2:24]2)[CH:7]=1
Reactant: OCC1(O)CCNCC1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCOCCO
Product: C[C@H](Nc1nc(Cl)cc(N2CCC(O)(CO)CC2)n1)c1ccc(F)cc1
Temperature: 135 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
150 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine and 97 mg of 4-(hydroxymethyl)piperidin-4-ol hydrochloride were dissolved in 3 ml of 2-ethoxyethanol, and 274 μl of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 135° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 194 mg of the objective compound as brown oil.