Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13]I>CS(C)=O>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Oc1cnc2ccsc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cnc2ccsc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of 6-hydroxythieno[3,2-b]pyridine (2.45 g, 16.2 mmol) in dry dimethylsulfoxide (15 ml), under a nitrogen atmosphere, was added 60% sodium hydride in mineral oil (0.75 g, 19 mmol) and let stir at room temperature for 1 hour. Methyl iodide (1.25 ml, 21 mmol) was added to this solution and it was stirred for an additional two hours. The solution was poured into ice/water and extracted with diethyl ether, washed with water, dried over anhydrous sodium sulfate, filtered and carefully evaporated to give an oily product (2.1 g, 78% yield) which was used as is.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13]2)=[N:6][CH:7]=1.[N:29]1([CH2:34][CH2:35][N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N(CC)CC)C>COCCOC.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:19]([C:14]1[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][C:10]2[CH:26]=[CH:27][CH:28]=[C:8]([C:5]3[N:4]=[CH:3][C:2]([C:39]4[CH:38]=[N:37][N:36]([CH2:35][CH2:34][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH:40]=4)=[CH:7][N:6]=3)[CH:9]=2)[N:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1ccc(Oc2ccccc2)nn1Cc1cccc(-c2ncc(Br)cn2)c1
Reactant: CC1(C)OB(c2cnn(CCN3CCCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc(Oc2ccccc2)nn1Cc1cccc(-c2ncc(-c3cnn(CCN4CCCC4)c3)cn2)c1
Temperature: 85 °C
Reaction time: 42 h

Procedure:
3.5 A suspension of 218 mg (0.50 mmol) of 2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-phenoxy-2H-pyridazin-3-one, 251 mg (0.75 mmol) of 1-(2-pyrrolidin-1-ylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (content 87%) and 230 mg (1.00 mmol) of tripotassium phosphate trihydrate in 2 ml of 1,2-dimethoxyethane and 1 ml of DMF is heated to 85° C. under nitrogen. 35.0 mg (0.05 mmol) of bis(triphenylphosphine)palladium(II) chloride and 9 μl (0.07 mmol) of triethylamine are then added and stirred at 85° C. for 42 hours. The reaction mixture is partitioned between THF and saturated sodium chloride solution. The organic phase is dried over sodium sulfate, evaporated and chromatographed on a silica-gel column with methanol/tert-butyl ether as eluent, giving 6-phenoxy-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one as yellowish amorphous material; ESI 520.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(Cl)c1

Procedure:
A mixture of 67 g (0.38 moles) of 3-chloro-4-hydroxyphenylacetic acid, 1.5 g of p-toluenesulfonic acid, and 250 ml of methanol was refluxed overnight, i.e., about 18 hours. The excess methanol was removed by vacuum to give a thick tawny oil. This oil was dissolved in ether, twice washed with water, and dried over anhydrous sodium sulphate. The ethereal solution was filtered, the ether removed and a tawny oil remained. Using as solvent 2.5% v/v methanol in chloroform and a silica gel matrix, thin-layer chromotography showed that the oil was essentially homogeneous, there being only a trace impurity present at the origin, which is believed to be unreacted acid. This oil was satisfactory for use as the starting material for forming the ether of Example 1B.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+:25]>C(O)C>[Na+:25].[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([O-:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)[O-])c1
Reaction time: 1 h

Procedure:
The 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid (Step D, 5.5 g, 17.6 mmol) was dissolved in abs ethanol (20 ml) by warming gently followed by addition of NaOH (0.705 g) at 0° C. temperature. The reaction mixture was stirred for one hour, concentrated in vaccuo and lyophilized to give as a white solid.
Reaction SMILES: ClC1C=C([N+]([O-])=O)C=C(Cl)C=1N1C=C2C=NC=C(F)C2=N1.[N:22]([C:25]1[C:30]([F:31])=[CH:29][N:28]=[CH:27][C:26]=1/[CH:32]=[N:33]/[C:34]1[C:41]([Cl:42])=[CH:40][C:39]([N+:43]([O-:45])=[O:44])=[CH:38][C:35]=1[C:36]#[N:37])=[N+]=[N-]>>[Cl:42][C:41]1[C:34]([N:33]2[CH:32]=[C:26]3[CH:27]=[N:28][CH:29]=[C:30]([F:31])[C:25]3=[N:22]2)=[C:35]([CH:38]=[C:39]([N+:43]([O-:45])=[O:44])[CH:40]=1)[C:36]#[N:37]
Reactant: N#Cc1cc([N+](=O)[O-])cc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Agent: O=[N+]([O-])c1cc(Cl)c(-n2cc3cncc(F)c3n2)c(Cl)c1
Product: N#Cc1cc([N+](=O)[O-])cc(Cl)c1-n1cc2cncc(F)c2n1
Temperature: 107 °C
Yield: 58 %

Procedure:
Following the procedure described for 2-(2,6-dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine, 2-{[1-(4-azido-5-fluoropyridin-3-yl)-meth-(E)-ylidene]-amino}-3-chloro-5-nitrobenzonitrile was heated at 107° C. for 3.5 hours. After purification by silica gel chromatography (0-5% methanol in DCM), the product was triturated 5 times with diethyl ether/cyclohexane (1:1) to afford the title compound as a yellow solid (3.31 g, 58% yield). LCMS (Method C): RT=2.89 min, m/z: 318 [M+H+].
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C:15]1[CH:16]=[C:17]([O:23][CH3:24])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=1>C(N(CC)CC)C>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([NH:14][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(N)cc1OC
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)cc1OC

Procedure:
Subject 1.35 g. (6.8 mmoles) of adamantane carboxylic acid chloride, 1.0 g. (6.5 mmoles) of 4-amino veratrole and 4.0 ml. of triethylamine to the process of Example 11 and obtain thereby the title product, m.p. 224°-226° C.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]COC)=[CH:7][C:6]=1[C@@H:15]1[CH2:19][C@H:18]([CH3:20])[CH2:17][C@@H:16]1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29]COC)=[CH:25][CH:24]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+].Cl>CO.BrCOC1C(O)=CC=C(C)C=1.CCOC(C)=O>[OH:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:21]2[C@H:16]3[CH2:17][C@@H:18]([CH3:19])[CH2:20][C@H:15]3[C:6]3[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=3[O:4]2)=[CH:28][CH:27]=1
Reactant: COCOc1ccc(C(=O)[C@H]2C[C@@H](C)C[C@H]2c2cc(OCOC)ccc2OCOC)cc1
Agent: Cc1ccc(O)c(OCBr)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Temperature: 50 °C
Yield: 69 %

Procedure:
To a solution of [2-(2,5-bis-methoxymethoxy-phenyl)-4-methyl-cyclopentyl]-(4-methoxymethoxy-phenyl)-methanone 10a (2.6 g, 5.8 mmol) in anhydrous methanol (232 mL) add p-toluenesulfonic acid (1.1 g, 5.8 mmol) and heat the resulting solution to 50° C. for 18 hours under nitrogen. Cool the reaction to ambient temperature and add bromocreosol green (10 mg) and sodium cyanoborohydride (1.82 g, 29.0 mmol). Add methanol saturated with HCl (gas) drop wise until yellow color is maintained. Stir the reaction one hour past the time when no more color change is observed. Quench the reaction with saturated sodium bicarbonate, add EtOAc, and wash the organic solution with sodium bicarbonate and brine. Dry the organic solution over sodium sulfate, concentrate in vacuo, and purify by flash chromatography (silica gel, 0-40% EtOAc/hexanes and 40% ethyl acetate/hexanes) to give 4-(4-Hydroxy-phenyl)-2-methyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol 11a (1.2 g, 4.0 mmol, 70%). 1H NMR (δ, 400 MHz, MeOD) 7.23 (d, 2H, J=8.4 Hz), 6.77 (d, 2H, J=8.4 Hz), 6.68 (d, 1H, J=8.8 Hz), 6.54 (d, 1H, J=2.6 Hz), 6.50 (dd, 1H, J=8.6, 2.9 Hz), 3.45-3.38 (m, 1H), 2.63-2.55 (m, 1H), 2.52-2.43 (m, 1H), 1.96-1.84 (m, 1H), 1.41-1.32 (m, 1H), 1.23-1.07 (m, 2H), 0.87 (d, 3H, J=6.6 Hz). MS calcd. 295.1; found (electrospray, M−1) 295.1. HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 10.35 min). HPLC (Chiralpak AD, 20-80% IPA/Heptane for 20 min; 1 mL/min; tR=4.37 min).
Reaction SMILES: NC1C([N+]([O-])=O)=C(N2CCN(CC(NC3SC=CN=3)=O)CC2)C(Cl)=CN=1.[NH2:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32](Cl)[C:31]([Cl:38])=[CH:30][N:29]=1.[C:39]1([CH:45]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH3:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)(C)C>[Cl:38][C:31]1[C:32]([N:50]2[CH2:51][CH2:52][N:47]([CH:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH3:46])[CH2:48][CH2:49]2)=[C:33]([N+:34]([O-:36])=[O:35])[C:28]([NH2:27])=[N:29][CH:30]=1
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Agent: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Solvent: CC(C)O
Product: CC(c1ccccc1)N1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Yield: 81.2 %

Procedure:
The method followed that used to prepare 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (Example 1, step 5), but using 2-amino-4,5-dichloro-3-nitropyridine (0.034 g, 0.16 mmol), isopropanol (3.5 ml), and 1-(1-phenylethyl)piperazine (0.048 g, 0.25 mmol). Purification of the crude product on a silica isolute column using a gradient of ethyl acetate in dichloromethane as eluant (10 to 20%) afforded the title compound as a yellow solid (0.047 g, 81%). 1H-NMR (500 Mz, DMSO-d6) 1.30 (d, J=6.7 Hz, 3H, CH3), 2.40 (br s), and 2.53 (br s, obscured by DMSO peak) (4H, piperazine N(CH2)2), 3.03 (br s, 4H, piperazine N(CH2)2), 3.45 (m, 1H, NCHCH3), 6.98 (s, 2H, 2-NH2), 7.25 (m, 1H) and 7.32 (m, 2H) (ArH), 8.06 (s, 1H, 6-H);
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16]Br)[C:8]=2[C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].[I-].[K+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]([CH3:32])=[N:30][N:31]=2)=[CH:23][C:22]=1[OH:33].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:33][C:22]3[CH:23]=[C:24]([C:27]4[O:28][C:29]([CH3:32])=[N:30][N:31]=4)[CH:25]=[CH:26][C:21]=3[CH3:20])[C:8]=2[C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: Cc1nnc(-c2ccc(C)c(O)c2)o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(C)o4)ccc3C)csc12
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A suspension of 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.29 g, 0.87 mmol) (from Example 1 supra), potassium iodide (0.14 g, 0.87 mmol), 2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenol (0.17 g, 0.9 mmol) (from Example 11 supra), potassium carbonate (0.27 g, 1.9 mmol) and 18-Crown-6 (10 mg, 0.04 mmol) (Aldrich) in N,N-dimethylformamide (5 mL) was heated at 65° C. in a sealed tube with magnetic stirring for 20 hours. After cooling, mixture was partitioned between ethyl acetate (2×100 mL) and water (2×100 mL). Aqueous layers were extracted with dichloromethane (2×100 mL). [Material was more soluble in dichloromethane than ethyl acetate.] Organic layers were washed with brine, then combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane then 20% ethyl acetate in dichloromethane as solvent) to give 4-chloro-3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.24 g, 62.4%).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][C:12]2[C:13]([O:18][CH3:19])=[N:14][N:15]([CH3:17])[CH:16]=2)[N:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O1CCOCC1>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:20])=[C:4]([NH:11][C:12]2[C:13]([O:18][CH3:19])=[N:14][N:15]([CH3:17])[CH:16]=2)[N:3]=1
Reactant: COc1nn(C)cc1Nc1nc(F)nc2[nH]cnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1COCCO1
Product: COc1nn(C)cc1Nc1nc(F)nc2c1ncn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a vigorously stirred suspension of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (7.25 g, 27.5 mmol, 1.00 eq) and potassium carbonate (7.61 g, 55.1 mmol, 2.00 eq) in 1,4-dioxane (92.0 mL), was added dimethyl sulfate (2.90 mL, 30.3 mmol, 1.10 eq) in a dropwise manner over 3 min. After 4 hr, additional portions of 1,4-dioxane (50.0 mL), potassium carbonate (3.80 g, 27.5 mmol, 1.00 eq), and dimethyl sulfate (1.00 mL, 10.4 mmol, 0.30 eq) were added to the reaction mixture. After a further 16 hr, the reaction mixture was concentrated in vacuo, diluted with water (120 mL), and stirred at ambient temperature for 1 hr. The resulting solids were filtered, washed with water (20 mL), and dried for 16 hr at 60° C. to give the title compound (6.42 g, 84% yield, >95% purity) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H) 3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C11H13FN7O 278.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][C:20]2[C:21]3[CH:38]=[CH:37][NH:36][C:22]=3[N:23]=[C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)[N:25]=2)[CH2:14]1.O>C(Cl)Cl.CN(C=O)C>[C:1]([CH2:3][C:4]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][C:20]2[C:21]3[CH:38]=[CH:37][NH:36][C:22]=3[N:23]=[C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)[N:25]=2)[CH2:14]1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: NC(=O)c1ccc(Nc2nc(NC3CCCNC3)c3cc[nH]c3n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC(=O)N1CCCC(Nc2nc(Nc3ccc(C(N)=O)cc3)nc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 46.9 %

Procedure:
To a suspension of cyanoacetic acid (46 mg, 0.54 mmol) in CH2Cl2 (1 mL) (containing 2 drops of DMF), oxalyl chloride (0.047 mL, 0.54 mmol) was added. The mixture was stirred at room temperature for 40 min. To the above solution cooled in an ice bath, a solution of 4-(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (18 mg, 0.051 mmol) and TEA (0.250 mL, 1.80 mmol) in DMF (2 mL) was added. The mixture was stirred for 2 h. Water was added. CH2Cl2 was removed in vacuo. The residue was purified by HPLC to give the titled compound (10 mg). MS 419.3 (M+H); UV 201.6, 311.9 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[C:19](OCC)(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[C:7]2[C:8](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]1=[O:26]
Reactant: COc1ccccc1CNc1ncccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cccnc2n(Cc2ccccc2OC)c1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 74.7 %

Procedure:
7.40 g (30.5 mmol) of 2-(2-methoxybenzylamino)nicotinaldehyde was dissolved in ethanol (100 mL), and 7.34 g (45.8 mmol) of diethyl malonate and 0.95 g (10.0 mmol) of piperidine were added thereto. The resulting mixture was stirred for 48 hours at 100° C. The mixture was cooled, and a solid precipitated thereby was separated by filtration. The solid was washed with hexane, and thus 7.71 g (yield: 75%) of the title compound was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:16]2[O:15][C:14]([CH3:18])([CH3:17])[O:13][C:12]=2[C:11]([C:19]([C:41]2[C:51]3[O:52][C:53]([CH3:56])([CH3:55])[O:54][C:50]=3[C:49]([C:57]([O:59][CH3:60])=[O:58])=[C:43]3[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=23)([C:21]2[C:31]3[S:32][C:33]([CH3:36])([CH3:35])[S:34][C:30]=3[C:29]([C:37]([O:39][CH3:40])=[O:38])=[C:23]3[S:24][C:25]([CH3:28])([CH3:27])[S:26][C:22]=23)O)=[C:10]2[C:6]=1[O:7][C:8]([CH3:62])([CH3:61])[O:9]2)=[O:4].B(F)(F)F.CCOCC.[Sn](Cl)Cl>[Zn]>[CH3:60][O:59][C:57]([C:49]1[C:50]2[O:54][C:53]([CH3:55])([CH3:56])[O:52][C:51]=2[C:41]([CH:19]([C:11]2[C:12]3[O:13][C:14]([CH3:18])([CH3:17])[O:15][C:16]=3[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]3[O:7][C:8]([CH3:61])([CH3:62])[O:9][C:10]=23)[C:21]2[C:31]3[S:32][C:33]([CH3:36])([CH3:35])[S:34][C:30]=3[C:29]([C:37]([O:39][CH3:40])=[O:38])=[C:23]3[S:24][C:25]([CH3:27])([CH3:28])[S:26][C:22]=23)=[C:42]2[C:43]=1[O:44][C:45]([CH3:48])([CH3:47])[O:46]2)=[O:58]
Reactant: COC(=O)c1c2c(c(C(O)(c3c4c(c(C(=O)OC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)OC)c5c3SC(C)(C)S5)SC(C)(C)S4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: Cl[Sn]Cl
Agent: FB(F)F
Agent: [Zn]
Solvent: CCOCC
Product: COC(=O)c1c2c(c(C(c3c4c(c(C(=O)OC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)OC)c5c3SC(C)(C)S5)SC(C)(C)S4)c3c1OC(C)(C)O3)OC(C)(C)O2

Procedure:
Bis-(8-methoxycarbonyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxol-4-yl)-mono-(8-methoxycarbonyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dithiol-4-yl)methanol (5 mg, 0.005 mmol) was dissolved in dry, degassed acetonitrile under an argon atmosphere. BF3.Et2O (2.0 μL, 0.011 mmol) and tin(II) chloride (3.0 mg, 0.016 mmol) were added. Amalgamated zinc (1.0 mg, 0.015 mmol) was added. The product was purified by flash chromatography (ether/heptane 5:1). Due to the small amount used the yield was not determined.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH:10](=[N:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: NCCN1CCNCC1
Solvent: Cc1ccccc1
Product: C(=NCCN1CCNCC1)c1ccccc1
Temperature: 25 °C

Procedure:
N-(2-Aminoethyl)piperazine (24.4 g) and benzaldehyde (26.9 ml) were dissolved in toluene (250 ml), and a Dean-Stark device was attached thereto, and the mixture was heated under reflux for 3 hours. After cooled to room temperature, a part (10 ml) of the reaction mixture was removed and concentrated to give N-[2-(benzylidene)aminoethyl]piperazine (1.4 g). Di (t-butyl) dicarbonate (45 g) was added to the remainder (about 240 ml) of the reaction mixture, and the mixture was stirred overnight at room temperature. 1 N aqueous potassium hydrogen sulfate (220 ml) was added thereto, and the mixture was vigorously stirred for 5 hours at room temperature, and the aqueous layer was partitioned by adding diethyl ether. The aqueous layer was basified by adding sodium hydroxide (solid), and the organic layer was partitioned by adding chloroform, washed with water, dried, and evaporated to give the title compound (14.9 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=O)[N:8]=[CH:7]2)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[CH:9][N:8]=[C:7]2[Cl:18])([O-:3])=[O:2]
Reactant: O=c1ncc2cc([N+](=O)[O-])c(Cl)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl
Temperature: 0 °C

Procedure:
4.00 g of the above crystalline 6-nitro-7-chloro-quinazolone was refluxed with 15 mL of phosphoryl chloride for 2 h, then the reaction mixture was poured into ice water, filtered and dried to obtain the intermediate 6-nitro-4,7-dichloro-quinazoline; The intermediate was dissolved into 30 mL of isopropanol, and 3.00 g of 3-chloro-4-(m-fluoro-benzyloxy)-aniline was added. The reaction mixture was reacted under reflux for 2 h and a lot of solid was deposited, which was filtered and dried under vacuum to obtain the solid product of 6-nitro-7-chloro-4-amino substituted quinazoline (3.83 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)([O:10][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(O)c2cccc(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 14.1 %

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate (0.4395 g, 1.29 mmol), 60% NaH (1.320 g, 33 mmol), and ethyl iodoacetate (5.237 g, 24.5 mmol) in THF (20 mL) was heated at 90° C. for 18 h and then cooled to rt. The reaction mixture was then quenched with saturated brine and extracted with ethyl acetate (3×), dried over Na2SO4. After the solvent was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford 0.0775 g (14%) of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-ethoxy-2-oxoethoxy)ethyl)piperidine-1-carboxylate. MS ESI +ve m/z 450 (M+Na).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[N:34]=[CH:35][C:36]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]2)=[O:23])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccc(Cl)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)nc1)N1CCN(C2CCC2)CC1
Yield: 26 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a off-white foam (26%).
Reaction SMILES: [C:1](=[O:10])([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])N>[Zn].II.CC(O)=O>[C:1](=[O:10])([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCOC(N)=O
Agent: II
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCOC(=O)OCCCCCC
Yield: 93.9 %

Procedure:
The procedure described in Example 11 is followed, but additionally 0.5 part of zinc-II acetate is included in the reaction mixture. Analysis by gas chromatography shows that within the same period of time 94% of the n-hexyl carbamate are converted and 20.3 parts of di-n-hexyl carbonate (93.9% of theory, based on converted n-hexyl carbamate), of boiling point 122°-124° C./4 mbar have been formed.