Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:19]=[CH:18]2.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:19]=[CH:18]3)[C:9]1=[O:13]
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)ccc21
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(cnn3COCC[Si](C)(C)C)c2)C1=O
Yield: 97688.7 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.095 g, 0.00058 mol) was reacted with 5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (0.170 g, 0.00058 mmol), 1,4-dioxane (10 mL), copper iodide (0.011 g, 0.000051 mol), trans-1,2-diamino cyclohexane (0.018 g, 0.00016 mol) and potassium carbonate (0.134 g, 0.00106 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 0.24 g of 1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-imidazolidin-2-one (97.5% yield).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8].[CH:13]([N:16]=[C:17]=[N:18][CH:19]([CH3:21])[CH3:20])([CH3:15])[CH3:14]>>[CH:13]([N:16]=[C:17]([NH:18][CH:19]([CH3:21])[CH3:20])[N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:7][CH3:8])[O:9][CH3:10])([CH3:15])[CH3:14]
Reactant: CC(C)N=C=NC(C)C
Reactant: CNCCC[Si](OC)(OC)OC
Product: CO[Si](CCCN(C)C(=NC(C)C)NC(C)C)(OC)OC
Reaction time: 2 h

Procedure:
A mixture of 60.5 g of N-methyl-(3-(trimethoxysilyl)propyl)amine (0.313 mol) and of 47.6 g of diisopropylcarbodiimide (0.376 mol, 20% excess) was heated for 3 h 30 min at 100° C. (amine conversion of greater than 99%). The final colorless mixture was devolatilized at 100° C. under 2 mbar for 2 h to give 99.5 g of a colorless, low-viscosity liquid corresponding to the expected guanidine.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][C:13]#[N:14].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>C1COCC1>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]([C:18]1[CH:19]=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[C:13]#[N:14]
Reactant: N#CCc1nc2ccccc2s1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a stirred suspension of NaH (60% in oil, 9.2 g, 0.23 mol) in dry THF (200 ml) was added drop wise under inert atmosphere a solution of 1,3-benzothiazol-2-yl-acetonitrile (20 g, 0.15 mol) in dry THF (200 ml). After 1 h30 stirring at r.t., a solution of 2,4-dichloropyrimidine (17.1 g, 0.15 mol) in dry THF (200 ml) was added dropwise. The reaction mixture was allowed to stir under inert atmosphere at r.t. until complete disappearance of the starting material. The reaction was quenched by addition of water and the THF was evaporated. Water was added and the suspension was slightly acidified with aqueous HCl 1M. The precipitate obtained was filtered off and washed thoroughly with water until neutral then with hexane to remove the oil. The crude solid was dried under vacuum at 40° C., affording 28 g (84%) of the title compound as a light brown powder: mp 246° C. dec.; MS: 286.8 (M+1); HPLC (Conditions a, 268 nm) 97%, rt.5.66 min; 1HNMR (DMSO-d6) δ 13.25 (br s, 1H, exchangeable), 8.09 (d, J=4.14 Hz, 1H), 7.90 (d, J=7.53 Hz, 1H), 7.61 (d, J=7.92 Hz, 1H), 7.39-7.34 (m, 1H), 7.20-7.15 (m, 1H), 6.96 (br d, 1H). CHN analysis: C13H7ClN4S: Calculated: C, 54.19%; H, 2.48%, N, 19.45%; Found: C, 53.35%; H, 2.77%; N, 17.62%.
Reaction SMILES: C(#N)C=CCCCCCCC.[CH2:12]([OH:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH3:26].CCCCCC.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([O:27][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:36])[CH3:35]
Reactant: CCCCC=CC=CCCCCCCCO
Reactant: CC(=O)OC(C)=O
Agent: CCCCCCCC=CC#N
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCCC=CC=CCCCCCCCOC(C)=O

Procedure:
The pentadecadiene (D) (5.9 g) in 200 ml methanol containing eight drops concentrated HCl was refluxed for 15 minutes. After the solution was cooled, 400 ml of water were added, and the mixture was extracted three times with hexane. The hexane extract was dried over sodium sulfate, and the hexane was removed with a rotary evaporator leaving 3.1 g of crude 8,10-pentadecadienol, which was purified by silica gel liquid chromatography. Unwanted side products were eluted with 10% ether/hexane, and the alcohol was eluted with 50% ether/hexane, giving 2.5 g (66% yield based on the decenenitrile (B)). 8,10-Pentadecadienol in 75 ml pyridine and 5 ml acetic anhydride was refluxed 1.5 hours. After the solution was cooled, 200 ml hexane was added, and the mixture was extracted successively with water, 6N hydrochloric acid (twice), and water. The pentane phase was dried over sodium sulfate, filtered, and the pentane was removed by rotary evaporation, leaving crude product, which was purified by silica gel liquid chromatography (elution in 10% ether/hexane); the yield was 2.8 g (94% based on the alcohol). The product was 39% EE and 61% EZ by GC analysis.
Reaction SMILES: [C:1]([O-:15])(=O)[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].[Ca+2].[C:17]([O-:31])(=O)[CH2:18][CH2:19][NH:20][C:21](=[O:29])[C@@H:22]([C:24]([CH2:27][OH:28])([CH3:26])[CH3:25])[OH:23].Cl.Cl.[NH2:34][CH2:35][CH2:36][S:37][S:38][CH2:39][CH2:40][NH2:41].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.C1C=CC=CC=1.O>[CH3:26][C:24]([C@@H:22]([OH:23])[C:21]([NH:20][CH2:19][CH2:18][C:17]([NH:34][CH2:35][CH2:36][S:37][S:38][CH2:39][CH2:40][NH:41][C:1]([CH2:2][CH2:3][NH:4][C:5]([C@H:6]([OH:7])[C:8]([CH2:11][OH:12])([CH3:9])[CH3:10])=[O:13])=[O:15])=[O:31])=[O:29])([CH2:27][OH:28])[CH3:25]
Reactant: NCCSSCCN
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO
Yield: 69.2 %

Procedure:
11.9g. of calcium pantothenate, 5.6g. of cystamine dihydrocloride and 7.7g. of 1-hydroxybenzotriazole were dissolved in a mixed solvent of 50ml. of pyridine, 10ml. of water and 25ml. of benzene, and thereafter pyridine (25ml.) solution of 10.5g. of dicyclohexylcarbodiimide was added thereto at a time, and then this was subjected to reaction at a temperature below 10° C for 1 hour and thereafter to reaction at a room temperature for 5 hours. Then the solvent was removed at a reduced pressure, and the residue thereof was added with 50ml. of water and the resultant deposited crystals were removed by filtration. Pyridine left in the filtered mother liquor was completely removed azeotropically with water. The residue thereof was added with 50ml. of water, and after cooling it, the deposited crystals was removed by filtration, and extracted two times with 20ml. of chloroform. The water layer was passed through a monobed column composed of 78ml. of strong acidic cation exchanger resin (Amberlite 1R-120B) [H+] and 150ml. of strong basic anion exchanger resin (Amberlite 1RA-410) [OH-], and washed out with water. The presence of the objective compound in the flowed out liquid was traced by refractometer. The eluted solution was concentrated under a reduced pressure and subjected to freeze drying, and thereby 9.6g. of pantethine in the form of pulverized crystal was obtained (69.2% yield).
Reaction SMILES: C(Cl)(=O)C.[Cl:5][C:6]1[N:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)=[CH:9]2>CO>[Cl:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][N:12]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(Cl)nc3c2)CC1
Solvent: CC(=O)Cl
Solvent: CO
Product: Clc1ccc2ncc(N3CCNCC3)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (4.3 mL, 60.5 mmol) was added to MeOH (11 mL) at 0° C., the resulting solution was stirred at 0° C. for 30 min. To this solution, tert-butyl 4-(6-chloro-1,5-naphthyridin-3-yl)piperazine-1-carboxylate (D-18) (207 mg, 0.59 mmol, 1.0 eq) was added, and the mixture was stirred at RT for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo to afford the desired product 2-chloro-7-(piperazin-1-yl)-1,5-naphthyridine (D-19), which was used for next reaction without further purification. 1H NMR (300 MHz, DMSO-d6) δ: 8.99 (d, J=2.7 Hz, 1H), 8.28 (d, J=8.7 Hz, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 3.68 (m, 4H), 3.22 (m, 4H); ESI-MS m/z: 249.06[M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][C:8]=2[CH3:16])=[O:6])[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:19]=[C:20]([NH2:27])[C:21]2[N:25]=[CH:24][NH:23][C:22]=2[CH:26]=1.[N+]1([O-])C=CC=CC=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:27][C:20]1[C:21]2[N:25]=[CH:24][N:23]([C:10]3[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[C:8]([CH3:16])[CH:9]=3)[C:22]=2[CH:26]=[C:18]([Br:17])[CH:19]=1
Reactant: Nc1cc(Br)cc2[nH]cnc12
Reactant: Cc1cc(B(O)O)ccc1C(=O)NC1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [O-][n+]1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(-n2cnc3c(N)cc(Br)cc32)ccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a stirred solution of [4-(cyclopropylcarbamoyl)-3-methylphenyl]boronic acid (13.95 g, 63.68 mmol) in DCM (160 mL) at rt was added under a nitrogen atmosphere 6-bromo-1H-benzimidazol-4-amine (6.75 g, 31.84 mmol), copper(II)acetate (11.57 g, 63.68 mmol), pyridine N-oxide (3.33 g, 35.02 mmol) and pyridine (7.55 g, 95.53 mmol). After stirring overnight at rt, the mixture was stirred at 40° C. for 3 days. Filtration through ALLOX, extraction with water and evaporation of the organic phase gave the crude product, which was purified by flash chromatography to yield 6 g 4-(4-amino-6-bromo-1H-benzimidazol-1-yl)-N-cyclopropyl-2-methylbenzamide (50%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.[N:19]1([C:25]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][N:29]=[CH:30]3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:22]1[CH2:23][CH2:24][N:19]([C:25]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:26]=3[CH:27]=[CH:28][N:29]=[CH:30]4)[CH2:20][CH2:21]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: c1cc(N2CCNCC2)c2ccncc2c1
Reactant: O=CCCCOc1nc2c(cc1F)CCC(=O)N2
Product: O=C1CCc2cc(F)c(OCCCCN3CCN(c4cccc5cnccc45)CC3)nc2N1

Procedure:
The title compound was prepared by reductive amination of 4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 5-piperazin-1-yl-isoquinoline using a procedure similar to Example A1′. MS: APCI: M+1: 450.2 (Exact Mass: 449.22).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:29][C:30]([CH3:32])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:30]([CH3:32])[CH3:29])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)C1CCCC1)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)C2CCCC2)CC1

Procedure:
Using alkylation method A, 3-chloro-N-[1-cyclopentyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (140 mg, 0.35 mmol) and acetone (0.25 mL, 3.5 mmol) afforded, after SCX purification, 67 g (44%) of the title compound.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H]([C@H](CO)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.C=[C:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1>>[OH:2][CH2:1][C@@H:32]1[CH2:31][CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@@H:33]1[C@H:34]1[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]1
Reactant: C[C@]12CCCCC1C[C@@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C[C@]12CCC(=O)CC1C[C@@H](CO)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
7α-Hydroxymethylandrostane-3,17-dione II-av was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-7α-hydroxymethyl-androstane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (I-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.71 (2H, m), 3.30 (1H, t), 2.50-1.25 (21H, m), 1.12 (3H, s), 0.85 (3H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:14]2[NH:13][C:12](=[O:15])[C@@H:11]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1.I[CH3:27]>C1COCC1>[CH3:3][O:4][C:5]1[C:14]2[N:13]([CH3:27])[C:12](=[O:15])[C@@H:11]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2c1NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c1N(C)C(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a suspension of sodium hydride (60 mg of 60% dispersion in mineral oil, hexane-washed, 1.5 mmol) in 5 mL of THF was added (±)-cis tert-butyl 6-methoxy-4-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 10, Part A (0.40 g, 1.25 mmol) in 4 mL of THF. The reaction was stirred at ambient temperature for 1 h, at which time gas evolution had ceased. Then there was added iodomethane (0.23 mL, 3.75 mmol) and the resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was quenched with 1N HCl and was extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford 0.38 g (91%) of the title compound which was used without purification.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[N:6]([CH3:13])[N:5]=1.[OH-].[Na+].Cl>CO>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]([CH3:13])[N:5]=1
Reactant: COC(=O)c1cc(OC(F)F)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(OC(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.97 mmol) of methyl 3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate are dissolved in 6.5 ml of methanol and 1.94 ml of 1M sodium hydroxide solution is added. The reaction mixture is stirred overnight at room temperature, then admixed with 1M hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. This gives 180 mg of 3-difluoromethoxy-1-methyl-1H-pyrazole-5-carboxylic acid (97%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:19][CH2:20][C:21]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][C:16]([F:18])=[CH:15][CH:14]=2)[N:1]=1
Reactant: Nc1cc(F)ccc1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2ccc(F)cc2nc(CCl)n1-c1ccccc1Cl
Yield: 82 %

Procedure:
Prepared according to Procedure B with 1c (500 mg, 1.89 mmol) and chloroacetyl chloride (0.45 mL, 5.67 mmol) in acetic acid (10 mL). Purified by extraction from aqueous K2CO3, followed by recrystallization from isopropanol to afford 501 mg of a yellow crystalline solid (82%). 1H NMR (CDCl3) δ: 8.32 (dd, J=6.0, 8.9 Hz, 1H); 7.59-7.66 (m, 1H); 7.50-7.55 (m, 3H); 7.44 (dd, J=2.4, 9.4 Hz, 1H); 7.27 (dt, J=2.5, 8.5 Hz, 1H); 4.37 (d, J=12 Hz, 1H), 4.07 (d, J=12 Hz, 1H). MS (ES): m/z 323.0 (M+).
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=O)=[CH:8][CH:7]=1.[CH2:16]([NH:18][CH2:19][CH2:20][OH:21])[CH3:17]>>[CH2:16]([N:18]([CH2:19][CH2:20][OH:21])[C:2](=[O:3])[C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[O:12])=[CH:14][CH:15]=1)[CH3:17]
Reactant: CCNCCO
Reactant: COC(=O)c1ccc(C2OCCO2)cc1
Product: CCN(CCO)C(=O)c1ccc(C=O)cc1
Reaction time: 1 h
Yield: 50.3 %

Procedure:
A solution of methyl 4-(1,3-dioxolan-2-yl)benzoate (0.63 g, 3.0 mmol) in 2-(ethylamino)ethanol (2.93 mL, 30.0 mmol) was heated in a microwave at 130° C. for 2 hours. The reaction mixture was partitioned between DCM and 1M aqueous hydrochloric acid and stirred vigorously for 1 hour. The organic phase was removed, washed with brine and passed through a hydrophobic frit. The solvent was evaporated at reduced pressure to afford the title compound (0.334 g, 50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[NH:12][CH:13]=2)[O:3]1.Br[CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:24]([O:23][CH2:22][CH2:21][CH2:20][N:12]1[CH:13]=[C:9]([B:4]2[O:3][C:2]([CH3:18])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=[C:11]1[C:14]([O:16][CH3:17])=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCCOCc1ccccc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1CCCOCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
A mixture of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (Compound 38F, 600 mg, 2.39 mmol) and 1-bromo-3-benzyloxypropane (575 mg, 2.51 mmol) in DMF (2.19 mL) was charged with cesium carbonate (778 mg, 2.39 mmol). The reaction mixture was allowed to stir at 70° C. for 16 hrs. The reaction mixture was diluted with water and then extracted with EtOAc (2×). The organic layer was washed with water (2×), brine (1×), dried over Na2SO4, filtered, concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→4% Ethanol in DCM] to afford 442 mg of the title compound (46%). 1H NMR (400 MHz, CD3OD) δ 7.26-7.37 (m, 5H), 7.25 (d, J=1.8 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 4.45 (s, 2H), 4.42 (t, J=6.8 Hz, 2H), 3.78 (s, 3H), 3.38 (t, J=5.9 Hz, 2H), 2.01 (t, J=6.2 Hz, 2H), 1.31 (s, 12H). MS (ESI): m/z 440.59 [M+H]+. UPLC: tR=1.60 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][O:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH3:44])[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][O:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])[C:41](=[O:42])[C:38]1[CH:39]=[CH:40][C:35]([CH3:44])=[CH:36][CH:37]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1noc2nc(C(NCCCNC(=O)OC(C)(C)C)C(C)C)n(Cc3ccccc3)c(=O)c12
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3onc(C)c3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 35 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A solution of {3-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (method 47) (100 mg, 0.213 mmol) in DCM (4 ml) was added p-toluoyl chloride (66 mg, 0.426 mmol) followed by triethylamine (65 mg, 0.639 mmol). The mixture was stirred at 30-40° C. for 2 days. The mixture was then diluted with DCM, washed with saturated sodium bicarbonate aq. The organic phase was dried, filtered, and concentrated. The crude oil was purified by ISCO (solvent: EtOAc-hexane) to give {3-[[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6 -yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester as white solid (115 mg, 0.196 mmol). m/z: 588 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH2:10].[N+](N[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)=[CH:17][N:16]=1)([O-])=O>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)=[CH:17][N:16]=1
Reactant: NCCSCc1nccs1
Reactant: COc1cccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Product: COc1cccc(Cc2cnc(NCCSCc3nccs3)[nH]c2=O)c1
Yield: 41.9 %

Procedure:
2-(2-Thiazolylmethylthio)ethylamine (2.00 g) and 2-nitroamino-5-(3-methoxybenzyl)-4-pyrimidone (1.58 g) were fused together at 130° for 4 hours. The mixture was triturated with hot water and the residue was recrystallised from 2-propanol to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone (0.93 g), m.p. 122°-4°. A sample was treated with hydrogen chloride in ethanol and after recrystallision from isopropanol/methanol it had m.p. 104°-6° and gave analytical data corresponding to a hemihydrochloride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][O:20][CH3:21])=[C:12]([CH:17]=1)[C:13](OC)=[O:14].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][O:20][CH3:21])=[C:12]([CH2:13][OH:14])[CH:17]=1
Reactant: COCOc1ccc(F)cc1C(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COCOc1ccc(F)cc1CO
Yield: 48.5 %

Procedure:
Lithium aluminum hydride (2.2 g) was added to a THF (200 ml) solution of the compound 324-1 (12.4 g), while the solution was stirred under cooling on ice. The obtained mixture was stirred at room temperature for 3 hours. Ice was added by portions to the reaction solution, and thereby excessive lithium aluminum hydride was decomposed. Thereafter, a small amount of 27% ammonium aqueous solution and Celite were added to the residue, and the obtained mixture was stirred at room temperature for 20 minutes. Magnesium sulfate was added to the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane/ethyl acetate=1:0 to 3:1), so as to obtain the title compound (5.23 g).