Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=1>CCO>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH:21][CH2:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCN)cc1
Reactant: BrCC1CCc2ccccc2C1
Solvent: CCO
Product: COc1ccc(CCNCC2CCc3ccccc3C2)cc1
Yield: 59 %

Procedure:
A solution of 2-bromomethyl-1,2,3,4-tetrahydronaphthalene (1.33 g, 5.91 mmol) and 4-methoxyphenethylamine (1.79 g, 11.8 mmol) in 50 ml of EtOH was refluxed for 48 hours. After removal of EtOH in vacuo, the residue was dissolved in 100 ml of CHCl3, washed with 10% K2CO3, H2O, sat'd brine, and then dried over Na2SO4. Filtration followed by evaporation of solvent gave a yellow oil, which was purified by chromatography (SiO2, MeOH:CHCl3, 5:95) to a give a yellowish oil (1.03 g, 58.9%). The product was converted to HCl salt, crystallization with MeOH/Et2O gave a white powder. mp 274-275° C.; Calcd for C20H25NO.HCl: C 72.37, H 7.91, N 4.22; Found C 72.40, H 7.76, N 4.13.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:11]([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:11])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cncc(O)c1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(OCc2ccccc2)c1
Temperature: 60 °C
Yield: 27.9 %

Procedure:
A mixture of 818 mg (5.34 mmol) of 5-hydroxynicotinic acid, 1.70 g (12.3 mmol) of K2CO3, and 1.0 mL (8.41 mmol) of benzyl bromide in 25 mL of DMF was heated at 60° C. under Ar for 16 h. The mixture was filtered through cotton, and the residue was dissolved in CHCl3. The organic layer was washed with water (2×30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography provided 363 mg of methyl 5-(benzyloxy)nicotinate in 28% yield as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[O:29]([C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](O)=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=2[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[S:17][C:10]=12
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(NC(=O)c5ccccc5Oc5ccccc5)cc4F)c3s2)CC1
Yield: 67 %

Procedure:
Prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 2-phenoxybenzoic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (10% MeOH in CH2Cl2) to afford 25 mg (67%) of the desired product. LRMS (ESI pos) m/e 593.3 (M+1). 1H-NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.48 (d, 1H), 8.36 (d, 1H), 7.87 (dd, 1H), 7.58 (s, 1H), 7.46 (t, 3H), 7.29 (m, 3H), 7.21 (d, 1H), 7.17 (m, 2H), 6.91 (d, 1H), 6.51 (dd, 1H), 3.60 (s, 2H), 2.52-2.71 (m, 8H), 2.32 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −126.7.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:12]=[C:13](\[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)/[C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:12]=[C:13](\[C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)/[C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
500 mg of (E)-3-(3-nitro-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-ene-nitrile were dissolved in 25 ml of acetic acid, and 5 g of zinc were added thereto and stirred for 30 minutes at room temperature. The reaction liquid was filtered and then concentrated. The concentrated liquid was purified by silica gel column chromatography (ethyl acetate:hexane--1.2 by volume) to obtain 457 mg of the intended compound. The yield was 99%.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Li+].CC([N-]C(C)C)C.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH3:27])[CH:21]=1.Cl>O1CCCC1>[CH2:26]([C:22]1[CH:21]=[C:20]([CH2:19][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH:25]=[CH:24][CH:23]=1)[CH3:27]
Reactant: CCc1cccc(CBr)c1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1cccc(CC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl acetoacetate (25 g) in tetrahydrofuran (800 ml) at 0° C. was added LDA (2.0M solution in heptanes/tetrahydrofuran/ethylbenzene) (194 ml). After 40 min the product from step (ii) (39 g) was added dropwise and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was acidified with 2N HCl and the organic phase was concentrated under reduced pressure. The residue was dissolved in diethyl ether and washed with water and saturated brine. The organic phase was collected, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 5-10% ethyl acetate in isohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH3:17]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:17])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 2-(4-methoxyphenyl)acetic acid (500 mg, 3.00 mmol) in DCM (30 ml) was added thionyl chloride (0.4 ml, 4.5 mmol) at 0° C. The reaction mixture was allowed to warm up to room temperature and continued to stirred overnight. Then aqueous ammonia (2 ml) was added to the reaction mixture. The white solid forming was filtered and dried under vacuum to obtained 350 mg (70%) of 2-(4-methoxyphenyl)acetamide as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][CH:29]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([NH:23][C:24]1[CH:29]=[N:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N)cn1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)ccc(F)c21
Product: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)ccc(F)c32)cn1
Yield: 88.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 11 using 5-benzyloxy-8-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.30 g) and 5-amino-2-isopropylpyridine (1.04 g) as starting materials, 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.83 g) was obtained. melting point: 184.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.[C:15]([O:18][C@@H:19]1[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:30]([O:36][C:37](=[O:39])[CH3:38])[C@@H:29]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[O:28][C@@H:20]1OC(=N)C(Cl)(Cl)Cl)(=[O:17])[CH3:16].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[C:15]([O:18][C@@H:19]1[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:30]([O:36][C:37](=[O:39])[CH3:38])[C@@H:29]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[O:28][C@H:20]1[O:14][CH2:13][C@H:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:12]1)(=[O:17])[CH3:16]
Reactant: OC[C@@H]1CC(c2ccc(Br)cn2)=NO1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OC[C@@H]2CC(c3ccc(Br)cn3)=NO2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h

Procedure:
To a solution of [(5S)-3-(5-bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (Intermediate 11, 0.369 g, 1.43 mmol) and 2,3,4,6-tetra-O-acetyl-1-O-(2,2,2-trichloroethanimidoyl)-α-D-glucopyranose (R. R. Schmidt and J. Michel, Angew. Chem. Int. Ed. Engl. 19 (1980), 731–732) in dry dichloromethane (20 mL) over molecular sieves (perled, 4 Å) was added dropwise at −20° C. a solution of trimethylsilyl trifluoromethanesulfonate in dichloromethane (0.02 M, 10 mL). The reaction mixture was allowed to reach room temperature over 2 hours, additional catalyst solution (5 mL) was added and it was left overnight at room temperature. The reaction was quenched by addition of triethylamine (3 drops), filtered and solvent was removed under reduced pressure. Chromatography on silica gel with hexanes/acetone 2:1 gave crude [(5S)-3-(5-bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside, as a mixture with intermediate 11. To a solution of this mixture in dry methanol (5 mL) was added potassium carbonate (20 mg) and it was vigorously stirred for 4 hours at room temperature. The reaction mixture was neutralized over Amberlite CG-50-II (H+-form), filtered and solvent was removed under reduced pressure. Chromatography on silica gel with dichloromethane/methanol 8:1 gave the product as a colourless solid (157 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2S)=[CH:5][CH:4]=1>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2ccnc2S)cc1
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(Cn2ccnc2)cc1

Procedure:
A mixture of 15.0 g (0.068 mole) of 1-(4-methoxybenzyl)-2-mercaptoimidazole and 80 g of Raney® nickel in 800 ml of ethanol was refluxed for 4 hr. The nickel was filtered off and the filtrate was evaporated. The residue was dissolved in 100 ml of 1N HCl and this solution was washed with diethyl ether. The aqueous layer was basified with NaHCO3 and extracted with ethyl acetate. The extracts were dried (K2CO3) and filtered and the solvent was evaporated, to give 1-(4-methoxybenzyl)imidazole as an oil, 8.7 g (68%). A solution of this oil in acetone was treated with hexamic acid and diethyl ether, and the hexamate salt was crystallized, mp 157°-159°.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:14][C:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2CC(O)=O)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[CH2:7]([O:14][C:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:1][C:2]([Cl:4])=[O:3])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Reaction time: 2 h

Procedure:
Oxalyl chloride (6.3 g, 50 mmol) is added dropwise over 5 minutes to a solution of N6 -(benzyloxycarbonyl)-9-(carboxymethyl)adenine (16.6 g, 50 mmol) dissolved in dichloromethane (200 mL). The reaction is stirred until gas evolution has ceased and then for an additional 2 hours. The reaction mixture is evaporated to an oil.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[C:25]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=3)[N:34]=[C:33]([C:49]3[CH:54]=[CH:53][C:52](Br)=[CH:51][CH:50]=3)[N:32]=2)=[CH:27][CH:26]=1>O1CCCC1.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>[C:25]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=3)[N:34]=[C:33]([C:49]3[CH:54]=[CH:53][C:52]([C:22]4[CH:23]=[CH:24][C:19]([C:16]5[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=5)=[CH:20][CH:21]=4)=[CH:51][CH:50]=3)[N:32]=2)=[CH:27][CH:26]=1
Reactant: Brc1ccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(-c2ccc(-c3ccc(-c4nc(-c5ccc(-c6ccccc6)cc5)nc(-c5ccc(-c6ccccc6)cc5)n4)cc3)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.3 mmol of butyl lithium was slowly added to 30 ml of tetrahydrofuran cooled to −78° C. in which prepared by dissolving 0.69 g of 4-bromobiphenyl. After stirring at −78° C. for 15 minutes, 0.91 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2.5 hours. A 1.35 g portion of 2,4-bis(4-biphenylyl)-6-(4-bromophenyl)-1,3,5-triazine prepared in Reference Example 3 and 0.12 g of tetrakis(triphenylphosphine)palladium(0) were dissolved in 60 ml of tetrahydrofuran and added to this solution, followed by stirring under heating reflux for 2 hours. The reaction solution was concentrated under a reduced pressure, and the thus obtained solid was purified by a silica gel column chromatography (developing solvent hexane:chloroform=2:1 to chloroform) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-biphenylyl)-6-[1,1′:4′,1″]terphenyl-4-yl-1,3,5-triazine (1.09 g, yield 71%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OCC3C=CC=CC=3)=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].O.C(O)(=O)C.[H][H]>CO.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCN1CCC(C2CCNCC2)CC1

Procedure:
A solution of 7.6 g (0.023 mol) of 1-ethyl-4-[1-(phenylmethoxycarbonyl)-4-piperidinyl]piperidine in a mixture of 70 ml of methanol, 30 ml of water and 10 ml of glacial acetic acid was hydrogenated in the presence of 10% palladium/charcoal at room temperature and 3 bar of hydrogen pressure until the uptake of hydrogen had ceased. After working up in the usual way the desired compound was obtained as a colourless oil in a quantitative yield.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>O1CCCC1>[CH2:1]([N:8]1[C:12](=[S:27])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCC(=O)N1Cc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1CCC(=S)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 1-benzyl-5-oxo-2-pyrrolidinecarboxylate (18.15 g, 77.8 mmol) and Lawesson's reagent (31.5 g, 77.9 mmol) were combined in dry tetrahydrofuran (100 mL) and stirred overnight at room temperature. The mixture was filtered, the filter cake was rinsed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (3:1, hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 250 (M+H)+; 1H NMR (CDCl3) δ 2.17 (m, 1H), 2.27 (m, 1H), 3.15 (m, 2H), 3.69 (s, 3H), 4.30 (dd, 1H), 4.37 (d, 1H), 5.73 (d, 1H), 7.32 (m, 5H).
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[N:30]1[C:38]([NH2:39])=[C:37]2[C:33]([NH:34][CH:35]=[N:36]2)=[N:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:39][C:38]1[N:30]=[CH:31][N:32]=[C:33]2[C:37]=1[N:36]=[CH:35][N:34]2[CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: Nc1ncnc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1)n1cnc2c(N)ncnc21
Yield: 39.7 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1, using 3-(1-bromoethyl)-4-(3-(morpholinosulfonyl)phenyl)-1H-isochromen-1-one (intermediate C9, 68 mg, 0.142 mmol), 9H-purin-6-amine (57.6 mg, 0.426 mmol) and K2CO3 (29.5 mg, 0.213 mmol) to give the title compound (30 mg, 37.1%). The resulting mixture was straightforward purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) The resulting product was further purified by Preparative HPLC (method 2) to give the chemically pure compound (10 mg, 13%) and a batch with lower purity (9 mg, 12%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>C(O)CCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: C1CSCCN1
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Yield: 70.4 %

Procedure:
A mixture of 1-chloro-4-nitro benzene (1.5 g, 9.5 mmol) and thiomorpholine (1.0 g, 9.7 mmol) was refluxed in n-butanol overnight. The solvent was evaporated under reduced pressure to give a residue, which on triturating with water gave a precipitate. The solid was filtered and washed thoroughly with water, followed by a small amount of pet ether to yield crude solid. Recrystallisation with ethanol yielded 4-(4-nitro-phenyl)-thiomorpholine (1.5 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[CH:31]1([NH:34][C:28](=[O:30])[CH2:27][N:25]2[CH:26]=[C:22]([C:19]3[C:16]4[CH:17]=[N:18][C:13]([C:3]5[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=5[Cl:12])=[CH:14][C:15]=4[NH:21][N:20]=3)[CH:23]=[N:24]2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)NC5CC5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and cyclopropylamine. LCMS (M+H)+=487.1/489.1.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([NH2:18])=[O:17])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][CH2:20][C:21]([CH2:23]Cl)=O>>[Cl:19][CH2:20][C:21]1[N:18]=[C:16]([C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=2)[O:17][CH:23]=1
Reactant: NC(=O)c1ccc2oc(-c3ccccc3)nc2c1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccc3oc(-c4ccccc4)nc3c2)n1
Yield: 65 %

Procedure:
In substantially the same manner as in Reference Example 47, 2-phenyl-5-benzoxazolecarboxamide was allowed to react with 1,3-dichloroacetone to give 5-(4-chloromethyl-2-oxazolyl)-2-phenylbenzoxazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave brown needles, mp 194-195° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[C:33](=[O:34])[C:32]4=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]4[C:30]3=[O:39])[CH:23]=2)[C:9]1=[O:40].[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl>C(OCC)(=O)C>[NH:41]([C:13]1[N:12]=[C:11]2[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]4[C:33](=[O:34])[C:32]5=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]5[C:30]4=[O:39])[CH:23]=3)[C:9](=[O:40])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[CH2:17][C:16]2=[CH:15][N:14]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1ccccc1Br)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 180 °C
Yield: 83 %

Procedure:
270 mg (0.44 mmol) of 3-(2-bromophenyl)-3,4-dihydro-7-(methanesulfonyl)-1-[3-(phthalimidomethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one was treated with 3 ml of aniline and the mixture heated to 180° C. for 20 minutes and cooled. 20 ml of ethyl acetate and 20 ml of 2M aqueous hydrochloric acid were added. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford 230 mg (83%) of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-[3-(phthalimidomethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a tan solid. [Mass spectrum (ESI)=632].
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O.[H][H]>>[CH3:8][C:6]1([CH3:9])[CH2:7][CH:2]([NH:1][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:1][CH:2]2[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]2)[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5]1
Reactant: OCCCCCCO
Reactant: [H][H]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
A mixture of 4-amino-2,2,6,6-tetramethylpiperidine and 1,6-hexanediol in a molar ratio of 4:1 is reacted in a 1-liter shaft oven which is filled with 500 ml of reduced copper chromite catalyst (Harshaw Cu 1107 of Harshaw Chemical Co, DE-5632 Wermelskirchen) at 180° C. and 30 bars of hydrogen hourly.