Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][NH:17][CH2:16][CH:15]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=3)=[O:32])[CH2:16][CH:15]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:10])[F:11]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CNCC(c2ccc(OC(F)(F)F)c(F)c2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(c2ccc(OC(F)(F)F)c(F)c2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1.74 g (5.42 mmol) of the compound from Example 92A were initially charged in 80 ml of dichloromethane and cooled to 0° C., and admixed with 1.5 ml (1.09 g, 10.8 mmol) of triethylamine and 1.09 g (5.42 mmol) of 4-nitrophenyl chloroformate. The reaction mixture was allowed to warm up slowly to RT and stirred at RT for 16 h. It was washed repeatedly with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 2.4 g (87% of theory)
Reaction SMILES: COC1C=CC(C[N:10]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][O:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11]2)=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[C:28]1([CH:27]2[CH2:26][O:25][C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]3)[CH2:11][NH:10]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OCC2c2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(c1ccccc1)CO2
Temperature: 70 °C
Yield: 92.1 %

Procedure:
To tert-butyl 8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (500 mg, 1.11 mmol), Pd (500 mg, 4.70 mmol) and ammonium formate (697 mg, 11.05 mmol) was added methanol. The reaction mixture was then heated at 70° C. for 16 hours. The reaction mixture was filtered through a plug of celite and the solvent was concentrated in vacuo to obtain tert-butyl 9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (340 mg, 93%) as an oil. ESI-MS m/z calc. 332.4. found 333.5 (M+1)+; Retention time: 1.21 minutes (3 min run).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])(=[O:3])[CH3:2].[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:17][CH:16]=[CH2:15])=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(C)=O)cc1C(=O)O

Procedure:
The reaction of methyl 5-acetyl-2-hydroxyl-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 5-Acetyl-2-allyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.94 (s, —CO2H); 8.21 (m, 1 arom. H); 8.06 (m, 1 arom. H); 7.20 (m, 1 arom. H); 6.02 (m, —CH═CH2); 5.50, 5.28 (2 d-like, CH═CH2); 4.73 (d-like, CH2—CH═CH2); 2.53 (s, CH3C═O). 13C-NMR (100 MHz, d6-DMSO): 195.91 (CH3C═O); 166.71 (C(OH)═O); 160.44; 133.22; 132.76; 131.12; 129.11; 121.46; 117.30; 113.35; 69.81; 26.42.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[N:9]=1.C(N(CC)CC)C.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[O:26])=[CH:22][CH:21]=2)[N:9]=1
Reactant: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc(-n3nc(-c4ccccc4O)nc3-c3ccccc3O)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3 g of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-benzoic acid (Example 5) and 1.25 ml of 1-chloro-N,N-2-trimethyl-1-propen-1-amine are stirred for 2 h in 50 ml of tetrahydrofuran. 2.2 ml of triethylamine and 1 ml of N-methylpiperazine are added and the mixture is stirred at room temperature for 48 h. It is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, {4-(3,5-bis(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-phenyl}-(4-methylpiperazin-1-yl)methanone remains as colorless crystals of m.p. 226-229° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH2:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.CO.O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:1][C:2]2[N:11]=[CH:10][C:9]3[CH2:8][CH2:7][C:6]4[C:12]([C:16]([NH2:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=4[C:4]=3[N:3]=2)=[CH:23][CH:22]=1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(N)ncc1CC2
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2ncc3c(n2)-c2c(c(C(N)=O)nn2C)CC3)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (244 mg, 1.0 mmol) in a mixture of glacial acetic acid/methanol/water (1:1:1) (30 mL) in a round-bottom flask were added p-methoxybenzaldehyde (0.44 mL, 450 mg, 3.0 mmol) and then 85% sodium cyanoborohydride (210 mg, 2.0 mmol). The solution was stirred at room temperature for 7 hours. At that time further amount of aldehyde (0.44 mL) and sodium cyanoborohydride (210 mg) were added and stirring was continued overnight. The reaction mixture was poured into ice-water (200 mL), the pH was adjusted to 10 by addition of saturated sodium carbonate and the solution extracted with ethyl acetate (4×20 mL). The collected organic extracts were washed with brine until neutral, with water and dried over Na2SO4.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:24][C@H:25]1[C@@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@@H:28]2[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]1.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([NH:24][C@H:25]2[C@@H:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C@@H:28]3[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]2)=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (5 g), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (8.5 g), water (15 mL) and sodium bicarbonate (10.6 g). The mixture was heated to about 100° C. and maintained at the same temperature for about 20 hours and completion of the reaction was monitored by TLC. After completion of reaction the mixture was cooled to 30° C. followed by addition of water (50 mL) and ethyl acetate (25 mL). The mixture was stirred for about 10 minutes and layers were separated. The aqueous layer was extracted with ethyl acetate (25 mL). Total organic layer was washed with water (50 mL). The organic layer was subjected to complete distillation under vacuum at 55° C. followed by addition of ethyl acetate (5 mL). The mixture was stirred for 20 minutes followed by addition of n-hexane (75 mL). The mixture was further stirred at room temperature for solid separation followed by isolation of solid by filtration and washing with n-hexane (10 mL). The solid isolated was subjected to drying under vacuum at 60° C. for 3 hours to afford the title compound in about 91% yield having HPLC purity of about 99.18%.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10](C(OC(C)(C)C)=O)[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:27]>C(O)CO>[C:12]1([C@H:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8][C:9]([NH2:10])=[N:27]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: N
Solvent: OCCO
Product: NC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 115 °C

Procedure:
A solution of intermediate 59 (1.0 g, 2.71 mmol) in ethylene glycol (10 mL) is saturated with ammonia and is heated in a pressure tube at 115° C. for 3 h. The reaction mixture is cooled to rt, and saturated with ammonia, and heated is heated at 115° C. overnight. The reaction mixture is cooled to rt, and the product is precipitated by the addition of addition of water to give 226 mg of the product 122. 1H NMR (DMSO-d6) δ 7.10-6.80 (m, 10H), 6.40 (bs, 3H), 5.10 (s, 2H); LC/MS: 2.89 min, m/z 238 (M++1).
Reaction SMILES: [C:1]([C:5]1[C:6]([C:16]([OH:18])=O)=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O/[N:43]=[C:44](/[C:46]1[CH:63]=[CH:62][C:49]([CH2:50][N:51]2[CH2:54][CH:53]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:52]2)=[CH:48][CH:47]=1)\[NH2:45]>C(#N)C>[C:1]([C:5]1[C:6]([C:16]2[O:18][N:45]=[C:44]([C:46]3[CH:47]=[CH:48][C:49]([CH2:50][N:51]4[CH2:52][CH:53]([C:55]([O:57][C:58]([CH3:59])([CH3:61])[CH3:60])=[O:56])[CH2:54]4)=[CH:62][CH:63]=3)[N:43]=2)=[N:7][O:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: CC(C)(C)c1c(C(=O)O)noc1-c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(C)(C)C)n3)cc2)C1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 4-tert-butyl-5-phenylisoxazole-3-carboxylic acid (25 mg, 0.102 mmol), HOBt (28.1 mg, 0.183 mmol), and diisopropylethylamine (0.071 mL, 0.408 mmol) in acetonitrile (1 mL) was added EDC (45.9 mg, 0.240 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 31.1 mg, 0.102 mmol). The reaction mixture was stirred at 80° C. for 5 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (3 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by preparative HPLC afforded tert-butyl 1-(4-(5-(4-tert-butyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)-azetidine-3-carboxylate.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(N1CCN(C2C=C(N[C:31]([C:33]3[C:34]4[N:35]=[CH:36][CH:37]=[N:38][C:39]=4[C:40]([C:43]4[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=4[Cl:51])=[CH:41][CH:42]=3)=[O:32])C=CC=2)CC1)C>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:31]([C:33]3[C:34]4[N:35]=[CH:36][CH:37]=[N:38][C:39]=4[C:40]([C:43]4[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=4[Cl:51])=[CH:41][CH:42]=3)=[O:32])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cc(OC)ccc4Cl)c4nccnc34)c2)CC1
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Product: CCN1CCN(c2ccc(NC(=O)c3ccc(-c4cc(OC)ccc4Cl)c4nccnc34)cc2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(4-ethylpiperazin-1-yl)-aniline (Step 1.9) and 8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid (Example 63). Title compound: ESI-MS: 502.1 [M]+; tR=3.50 min (System 3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[N+:12]([O-])([OH:14])=[O:13].O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)c1ccccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a solution of the 1-(2-fluoro-phenyl)-propan-1-one (99 mmol) in concentrated sulfuric acid (80 ml) cooled down to −30° C. was added slowly fuming nitric acid (8 ml) over 20 min and the solution was stirred at −30° C. for 15 min. The mixture was slowly poured into a stirred mixture of 200 ml of water and 400 g of ice. The aqueous phase was extracted with ethyl acetate, the organic layer was extracted again with water and aqueous 1 M NaHCO3-solution. The organic layer was dried over Na2SO4, evaporated and the residue was chromatographed on silica using a mixture of heptane and ethylacetate as eluent to afford 16.5 g of the pure nitro intermediate XII-1. MS (ESI): m/z=198.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:13].CN(C)C(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[C:2]([Br:1])[N:3]=2)=[CH:18][CH:17]=1)[CH3:13]
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Nc2nc(Br)cn3ccnc23)cc1
Temperature: 160 °C

Procedure:
A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (0.18 mol), 4-aminobenzoic acid ethyl ester (2) (0.18 mol), and N,N-dimethylacetamide (30 mL) is heated at 160° C. for 30 min. The mixture is cooled to room temperature, treated with ethyl acetate (150 mL), stirred, and filtered to afford an orange/brown solid. This solid is slurried with ethyl acetate and saturated sodium bicarbonate solution to give 4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid ethyl ester (18) freebase.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C[N:14](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:14])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To indole-2-carboxylic acid (1e) (500 μL, 0.2 M in anhydrous DMF) was added HATU (250 μL, 0.4 M in anhydrous DMF) and Et3N (50 μL, 2.0 M in anhydrous DMF) and stirred for 5 minutes at room temperature. The desired amine (R6—NH2) was dissolved in 520 μL anhydrous DMF and added to the reaction mixture. The reaction mixture was stirred for two hours at 45° C. and the solvent was evaporated in vacuo and the residue was purified via preparative HPLC to obtain the desired product indole-2-carboxamide (I).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[C:5]([CH3:16])=[C:4]([CH3:17])[CH:3]=1.[C:18](O)(=[O:20])C.C1N2CN3CN(C2)CN1C3.O>C1(C)C=CC=CC=1>[CH:18]([C:3]1[C:4]([CH3:17])=[C:5]([CH3:16])[C:6]2[C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:13])[C:11]=2[C:2]=1[OH:1])=[O:20]
Reactant: Cc1cc(O)c2c(c1C)C(C)(C)CCC2(C)C
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Formrylation. 1-Hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (15 g, 0.0646 mol) was stirred with glacial acetic acid (100 mL), and hexamethylenetetramine (15 g, 0.107 mol) was added in one portion. The mixture was heated at 100° C. for 2 h. Hot water (100 mL) was added and the heating continued for an additional 0.5 h at 100° C. The mixture was cooled to 20° C., toluene (25 mL) was added, and the mixture was stirred vigorously. The organic layer was separated, washed with water (2×10 mL), then neutralized with 5% NaHCO3 solution and finally washed with brine (10 mL). The solvent was removed by distillation, and the residue crystallized from hexane, to give 2-formyl-1-hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (8.8 g), GLC purity 94%. 1H-NMR (CDCl3) δ12.94 (1H, s), 10.36 (1H, s), 2.43 (3H, s), 2.36 (3H, s), 1.65 (4H, s), 1.48 (6H, s), 1.46 (6H, s). 13C-NMR (CDCl3) δ195.4 (1C, d), 161.4 (1C, s), 156.0 (1C, s), 138.0 (1C, s), 131.9 (1C, s), 126.6 (1C, s), 116.7 (1C, s), 40.2 (1C, t), 37.9 (1C, t), 36.5 (1C, s), 35.1 (1C, s), 29.5 (2C, q), 28.1 (2C, q), 19.3 (1C, q), 14.1 (1C, q). IR (KBr) 1628 cm-1, MS (m/e) 260.3 (M+, 38.6), 245.2 (100.0), 175.1 (28.7), 189.1 (20.1).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([Sn:11]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])O)[CH2:8][CH2:9][CH3:10].O>C1(C)C(C)=CC=CC=1>[C:1]([O:6][Sn:11]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCC[Sn](O)(CCCC)CCCC
Reactant: C=C(C)C(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: C=C(C)C(=O)O[Sn](CCCC)(CCCC)CCCC
Yield: 64 %

Procedure:
Methacrylic acid (0.1 mol) and tri-n-butylhydroxystannane (0.1 mol) were dissolved in xylene and subjected to reaction. The water that formed as the reaction proceeded was removed together with the solvent by distillation. The by-product of the reaction was distilled off under vacuum and the residue was dried under vacuum to obtain tri-n-butylstannyl methacrylate (m.p. 46° C.; yield, 64%). This tri-n-butylstannyl methacrylate and ethyl methacrylate were put into a round-bottom flask at a molar ratio of 1:1 and xylene was added to achieve a concentration of ca. 50%. Benzoyl peroxide (1 mol % of the sum of tri-n-butylstannyl methacrylate and ethyl methacrylate) dissolved in xylene was charged into a dropping funnel. After equipping the flask with this funnel, the benzoyl peroxide solution was dripped in an amount of about 10% of the total quantity of the solution. Thereafter, the flask was heated to the reflux temperature and the remaining polymerization initiator was slowly added dropwise until the reaction was completed in 8 hours. After the reaction, the content of the flask was added to n-hexane and subjected to re-precipitation. The resulting precipitate was recovered and dried to obtain a solid product, which was slowly added to ice water and reprecipitated. The precipitate was recovered and dried to obtain poly(tri-n-butylstannyl methacrylate-ethyl methacrylate). Yield, 80%, Mn, 48,000; Mw/Mn=1.9, IR (ν cm-1), 1720, 1160, 760, 700; atomic absorption spectrum (Sn content), 24.90 (found) and 24.98 (calculated).
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[C:13]2[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:7][S:6]1)[CH3:4].[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([F:40])[CH:34]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@@H:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]([N:17]2[CH2:16][CH2:15][N:14]([C:12]3[C:13]4[CH:5]([CH2:3][CH3:4])[S:6][CH2:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:19][CH2:18]2)=[O:30])=[CH:34][C:35]=1[F:40]
Reactant: CCC1SCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)c(F)c4)NC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 5-ethyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (50 mg, 0.15 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoic acid (49 mg, 0.15 mmol) in DCM (10 mL) and triethylamine (1 mL) was added HBTU (59 mg, 0.15 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with DCM/ethyl acetate (1:1) to give tert-butyl (R)-3-(4-chloro-3-fluorophenyl)-1-(4-(5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (80 mg, 90%). 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, 1H), 7.40-6.90 (m, 3H), 5.36 (m, 1H), 4.82 (m, 1H), 4.65 (m, 1H), 4.12 (m, 1H), 3.90-3.18 (m, 8H), 3.04-2.89 (m, 2H). 1.95 (m, 1H), 1.57 (m, 1H), 1.42 (s, 9H), 0.94 (m, 3H). MS (APCI+) [M+H]+ 551.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N].C(=O)([O-])[O-].[K+].[K+].IC.[NH:16]1[CH:21]=[CH:20][CH:19]=NC1=O.ClC1C=CC(CNC(C(=COC)C(OC)=O)=O)=CC=1>CC(C)=O>[N:1]1[C:2]2[C:3](=[CH:19][CH:20]=[CH:21][N:16]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=c1nccc[nH]1
Reactant: [N]c1ccccn1
Agent: COC=C(C(=O)NCc1ccc(Cl)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: c1cnc2ncccc2c1

Procedure:
4,7-Dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamide. The preparation of specific examples of heterocycle W16.1 is described in Chart BE. 2-Amino-4-bromopyridine BE.1 is reacted with Boc-anhydride in dichloromethane toafford BE.2. The resulting Boc-protected amine is then oxidized with peroxybenzoic acid (Justus Liebigs Ann. Chem. 1972, 758, 111) to afford hydroxypyridine BE.3. The pyridyl nitrogen is then alkylated in the presence of potassium carbonate and iodomethane with acetone as solvent to afford BE.4. The Boc group is then removed under standard deprotection condition to afford BE.5. The pyrimidone BE.5 is then cyclized with methyl 2-(((4-chlorobenzyl)amino)carbonyl)-3-methoxy-2-propenoate to afford naphthyridine BE.6. Reaction of BE.6 with an alkylating agent (e.g. iodomethane) in the presence of potassium carbonate with acetone as solvent affords compounds such as BE.7. Compound BE.7 is then coupled through a modified Sonogashira coupling (Linstrumelle, G.; et. al, Tetrahedron Lett, 1993, 34 6403) with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) to afford the alkyne derivative BE.8. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula BE.9 (Z=CH2OH).