Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[CH:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].[OH-].[Na+]>C(OCC)C>[C:1]1([C:7]([CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[CH:8][CH2:9][CH2:10][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCC=C(c1ccccc1)C1Cc2ccccc2C1
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCN(CC)CCC=C(c1ccccc1)C1Cc2ccccc2C1
Temperature: 100 °C

Procedure:
To a solution of 29.5 g. of 1-phenyl-1-(2-indanyl)-4-chloro-1-butene in 125 cc. of 95 percent (v/v) ethanolbenzene (commercial 2B ethanol) was added 100 cc. of diethylamine in one portion. The reaction mixture was shaken and heated in a sealed bomb to about 100° C for 16 hours. The reaction mixture was cooled to about 25° C. and the solvent was removed under reduced pressure to afford the product as an oily residue. The oil was dissolved in 400 cc. of diethyl ether and shaken with 5N sodium hydroxide and washed with water. The ethereal solution was dried and the solvent was removed under reduced pressure, affording 1-phenyl-1-(2-indanyl)-4-diethylamino-1-butene.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][C:48]([NH:50][CH:51]([CH3:53])[CH3:52])=[O:49]>>[CH:51]([NH:50][C:48](=[O:49])[CH2:47][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)([CH3:53])[CH3:52]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)NC(=O)CCl
Product: C=C(C)[C@@H]1CC[C@]2(NCC(=O)NC(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 2-chloro-N-isopropylacetamide as the alkylating reagent in Step 1. The product was isolated as a white solid (50 mg, 81%). LCMS: m/e 629.46 (M+H)+, 2.60 min (method 10). 1H NMR (400 MHz, Acetic acid d4) δ ppm 7.99 (d, J=8.53 Hz, 2H), 7.26 (d, J=8.53 Hz, 2H), 5.34 (d, J=4.77 Hz, 1H), 4.84 (s, 1H), 4.72 (s, 1H), 4.15 (d, J=15.31 Hz, 1H), 4.06 (dt, J=13.11, 6.62 Hz, 1H), 3.85 (d, J=15.31 Hz, 1H), 3.07-2.77 (m, 1H), 2.41-1.26 (m, 22H), 1.74 (s, 3H), 1.24 (s, 3H), 1.16 (d, J=6.53 Hz, 6H), 1.10 (s, 3H), 1.06 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].Cl.C(N(CC)CC)C>C(#N)C>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[C:20]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH2:24][CH2:25]1)=[O:9]
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Reactant: COC(=O)c1ccccc1NC(=O)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)c(OC)c2)CC1

Procedure:
10.06 Grams of methyl o-(α-chloroacetylamino)benzoate, 15.2 g of N-(3,4-dimethoxybenzoyl)piperzine.monohydrochloride and 16 g of triethylamine were suspended in 55 ml of acetonitrile, and the mixture was reacted at 49°-50° C. for 4 hours. After completion of the reaction, the reaction mixture was ice-cooled, and the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 14.68 g of o-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169.0° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([CH:24]([N:26]4[CH2:30][CH2:29][C@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27]4)[CH3:25])[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].[ClH:39]>C(Cl)Cl.CC(O)C>[ClH:39].[ClH:39].[ClH:39].[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([CH:24]([N:26]4[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]4)[CH3:25])[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1)N1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1)N1CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of tert-butyl (3S)-1-(1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.028 g, 0.0544 mmol) in DCM (2 mL) was added 5 N HCl (0.33 ml, 1.63 mmol) in IPA. The mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure to give (3S)-1-(1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine tri-HCl salt (0.027 g, 94.7%) as solid. LCMS APCI (+) m/z 415 (M+H).
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16]O)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].CCN(CC)CC.S([Cl:31])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][Cl:31])=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CO)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CCl)o1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-yl-methanol (760 mg, 2.95 mmol) in dry CH2Cl2 (15 mL) was treated at 0° C. with Et3N (0.53 mL, 3.82 mmol) followed by DMAP (36 mg, 0.30 mmol) and Ms-Cl (0.30 mL, 3.73 mmol). After stirring at 0° C. until reaction completion, the reaction was quenched with water (50 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-chloromethyl-oxazole as a yellow oil. The crude material (2.95 mmol) was dissolved in dry DMF (15 mL) and treated with NaN3 (205 mg, 3.01 mmol) at 80° C. for 40 h. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-azidomethyl-2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazole as a yellow oil. LC-MS-conditions 02: tR=1.12 min; [M+H]+=283.55.
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.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[CH:16][S:15][C:14]=1[NH:13][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)#[N:20]
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: N#Cc1ccsc1N
Product: COc1ccc(CC(=O)Nc2sccc2C#N)cc1

Procedure:
N-(3-cyanothiophen-2-yl)-2-(4-methoxyphenyl)acetamide was prepared from 2-(4-methoxyphenyl)acetic acid (1.37 g, 8.29 mmol) and 2-aminothiophene-3-carbonitrile (1.03 g, 8.29 mmol) according to protocol B. Retention time (min)=2.150, method [1], MS(ESI) 273.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[CH2:17]([C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([CH:31]=O)[CH:21]=1)[CH2:18][CH3:19]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:31][C:22]2[CH:21]=[C:20]([CH2:17][CH2:18][CH3:19])[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:23]=2)[CH2:12][CH2:13]1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Product: CCCc1cc(CNCCN2CCN(c3ccccc3F)CC2)nn1-c1ccccc1
Yield: 59.3 %

Procedure:
Compound 63 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1cccs1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1cccs1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-t-butyl-N-(2-thiophenecarbonyl)hydrazine (1 g) was dissolved in 10 ml toluene and treated with 50% aqueous sodium hydroxide (1.0 g) and water (2 ml) followed by benzoylchloride (0.8 g). After stirring for 14 hours at room temperature, the solid product, N'-t-butyl-N-(2-thiophenecarbonyl)-N'-benzoylhydrazine, was removed by filtration and washed with water: m.p. >190° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[C@@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:40]([NH:43][CH2:44]CO)(=[O:42])[CH3:41]>O1CCCC1.C(OCC)(=O)C>[C:40]([NH:43][CH2:44][CH2:23][O:22][C:20]([C:5]1[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]([C:8]([OH:10])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:24])=[O:21])(=[O:42])[CH3:41]
Reactant: CC(=O)NCCO
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@@H]1c1cccc([N+](=O)[O-])c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCOC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
The authentic (R)-form of the title compound was prepared as follows. That is, 5 mg of (S)-(+)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid prepared according to the method described by Shibanuma et al. (Chem. Pharm. Bull., 28(9), 2809-2812 (1980)) was dissolved in 0.5 ml of tetrahydrofuran. Then 2 μl of isobutyl chloroformate was added to the solution. After stirring for 10 minutes, 6 μl of triethylamine and 30 μl of N-acetyl-ethanolamine were added to the mixture followed by stirring for further 2 hours. After 5 ml of ethyl acetate was added to the reaction mixture, the mixture was washed with water and the resulting organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue thus obtained was purified on a preparative silica gel TLC (developing system, toluene-acetone; 1:1) to obtain 3 mg of the authentic (R)-form. The thus obtained authentic (R)-form compound showed the same residence time (14.0 minutes; moving phase 2.5% isopropanol/0.01M phosphate buffer (pH 7.1), flow rate: 0.8 ml/min) as that of the title compound obtained above on the column for optical resolution described above. With respect to the (S)-form, the residence time was 8.4 minutes under the same conditions.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[N:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([C@@H:31]([NH:33][C:34](=[O:36])[CH3:35])[CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>CN1C(=O)CCC1>[C:13]([C:12]1[C:11]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([C@@H:31]([NH:33][C:34](=[O:36])[CH3:35])[CH3:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[N:18][CH:17]=[CH:16][CH:15]=1)#[N:14]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncccc3C#N)CC2)cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
50 μL (0.29 mmol) DIPEA are added to a mixture of 14 mg (0.10 mmol) 2-chloronicotinnitrile and 29 mg (0.11 mmol) (S)-N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) in 1.45 mL NMP. The mixture is stirred at 130° C. overnight. Subsequently the solvent is removed in vacuo, the residue is taken up in DMF and the mixture is purified using reversed phase HPLC (water/MeOH, 0.1% TFA) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.CC(C)([O-])C.[K+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>CC(N(C)C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[CH3:9])[CH:20]=[CH:19][N:18]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Cc1cc(N)ccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(N)ccc1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
A solution of 4-amino-2-methyl-phenol (4.25 g, 34.5 mmol) in dimethylacetamide (50 mL) was degassed in vacuo and blanketed with argon. Potassium tert-butoxide (5.0 g, 44.6 mmol) was added and the reaction mixture was de-gassed a second time and stirred at RT under argon for 30 min. 2,4-Dichloro-pyridine (4.6 g, 31.3 mmol) was added and the mixture was heated to 100° C. overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 4-(2-chloropyridin-4-yloxy)-3-methylbenzenamine (4.5 g, 56% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=5.2 Hz, 1H), 6.75-6.80 (m, 3H), 6.45-6.50 (m, 2H), 5.15 (s, 2H), 1.92 (s, 3H); MS (ESI) m/z: 235.1 (M+H+).
Reaction SMILES: [C:1]([C:9]1[N:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[O:17])=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[N:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[O:17])=[N:13][CH:14]=1
Reactant: COc1ccc(C)cc1NC(=O)Nc1cnc(C(=O)c2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C)cc1NC(=O)Nc1cnc(C(O)c2ccccc2)cn1
Reaction time: 12 h
Yield: 91 %

Procedure:
To a stirred solution of 1-(5-benzoyl-pyrazin-2-yl)-3-(2-methoxy-5-methyl-phenyl)-urea (22 mg; 0.061 mmol) in methanol (1 mL) was added sodium borohydride (10 mg; 0.3 mmol). After stirring for 12 hours, the reaction diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), brine (30 mL), then dried (MgSO4), and filtered. The filtered material was concentrated under reduced pressure to yield a white solid (91% yield). 1H NMR (400 MHz, CDCl3) δ8.48 (br s, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.25-7.45 (m, 5H), 6.89 (d, 1H), 6.80 (d, 1H), 5.85 (d, 1H), 3.88 (s, 3H), 2.37 (s, 3H). LRMS (ESI, Positive) m/e 365.24 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[C:14]([NH2:17])(=[NH:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:15][C:14]1[N:17]=[CH:4][C:3]2[C:2](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[N:16]=1
Reactant: CC(=N)N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ncc2ccc([N+](=O)[O-])cc2n1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
2-Fluoro-4-nitrobenzaldehyde (1.00 g, 5.92 mmol) and acetamidine hydrochloride (0.783 g, 8.28 mmol) were added to a suspension of activated 4 Å MS (1.2 g) in acetonitrile (60 mL). K2CO3 (1.14 g, 8.28 mmol) was then added and the reaction was heated to reflux for 4 h. The reaction was then cooled to 25° C. and filtered through celite rinsing with CH2Cl2. The crude product was purified by flash chromatography on silica eluting with 0-10% acetone in CH2Cl2 to give 0.386 g of compound 25A as a yellow solid.
Reaction SMILES: C([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([F:28])[F:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CC(O)=O.[OH2:35].[Cl:36]N1C(C)(C)C(=O)N(Cl)C1=O.[OH2:47]>C(Cl)Cl>[F:27][CH:26]([F:28])[C:23]1[CH:24]=[CH:25][C:20]([C:13]2[C:12]3[C:17](=[CH:18][C:9]([S:8]([Cl:36])(=[O:47])=[O:35])=[CH:10][CH:11]=3)[N:16]=[C:15]([CH3:19])[N:14]=2)=[C:21]([O:29][CH3:30])[CH:22]=1
Reactant: COc1cc(C(F)F)ccc1-c1nc(C)nc2cc(SCc3ccccc3)ccc12
Reactant: O
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(F)F)ccc1-c1nc(C)nc2cc(S(=O)(=O)Cl)ccc12
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
A solution of 7-(benzylthio)-4-(4-(difluoromethyl)-2-methoxyphenyl)-2-methylquinazoline (0.380 g, 0.899 mmol) in 11 mL DCM and 0.22 mL (3:2 HOAc/water) solution was cooled to 0° C. and was treated with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.354 g, 1.799 mmol). After stirring for 15 minutes, LC/MS showed mostly product, so the reaction mixture was diluted with water. The layers were separated, and the organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography gave 4-(4-(difluoromethyl)-2-methoxyphenyl)-2-methylquinazoline-7-sulfonyl chloride (0.180 g, 0.451 mmol, 50.2% yield) as a white solid. (M+H)+=399.0.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([Sn:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O>[SH:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5].[CH2:16]([Sn+2:15][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[SH:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5]
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Reactant: O=C(O)CCS
Solvent: O
Product: CCCCCCCC[Sn+2]CCCCCCCC
Product: O=C([O-])CCS
Temperature: 60 °C

Procedure:
In a kneading drier, 4.27 kg of β-mercaptopropionic acid are added by spraying to 14.53 kg of dioctyltin oxide over a period of 6 minutes. The mixture thus obtained is heated at 60° C. for a period of 20 minutes with thorough mixing and under a pressure of 120 hPa (=120 mbar), during which the water of reaction formed escapes. The mixture is then cooled to room temperature while thorough mixing of the product is continued. Dioctyltin β-mercaptopropionate is obtained as a white free-flowing solid.
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[C:13]([Br:16])[C:12]([Cl:17])=[C:11](F)[N:10]=1.[CH3:19][C:20]([NH2:27])([CH3:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23].C1C=CC=CC=1>CCCCCC>[NH2:8][C:9]1[C:14]([F:15])=[C:13]([Br:16])[C:12]([Cl:17])=[C:11]([NH:27][C:20]([CH3:26])([CH3:19])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[N:10]=1
Reactant: Nc1nc(F)c(Cl)c(Br)c1F
Reactant: CC(C)(C)CC(C)(C)N
Solvent: CCCCCC
Solvent: CN1CCCC1=O
Solvent: c1ccccc1
Product: CC(C)(C)CC(C)(C)Nc1nc(N)c(F)c(Br)c1Cl
Temperature: 140 °C
Reaction time: 82 h
Yield: 46 %

Procedure:
To 6 ml of N-methylpyrrolidone were added 2.4 g of 2-amino-4-bromo-5-chloro-3,6-difluoropyridine and 3.5 g of 1,1,3,3-tetramethylbutylamine, and the mixture was stirred at 140° C. for 82 hours and allowed to cool. 50 ml of the mixed solution of benzene and n-hexane (1:1, v/v) was added, and the solution was washed twice with 400 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue was subjected to column chromatography (silica gel, 30 g; eluent: chloroform:n-hexane, 1:1) to obtain 1.6 g of the title compound as a colorless oily residue.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH2:17]([O:20][NH2:21])[CH:18]=[CH2:19].[OH-].[Na+]>O1CCOCC1.O>[CH2:17]([O:20][NH:21][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1)[CH:18]=[CH2:19]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: C=CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCONc1nc(NCCC)nc(NCCC)n1
Temperature: 60 °C
Yield: 88.4 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (2.00 g, 8.71 mmol), O-allyl-hydroxylamine hydrochloride (1.91 g, 17.42 mmol) and NaOH (0.70 g, 17.42 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was heated at 60° C. for 4 h. The volatiles were removed under reduced pressure. Saturated NaHCO3 solution (100 mL) was added to the residue and the mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLIII, 2.05 g, 88% yield). ESI-MS (m/z) 267 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:6]=2[N:7]=1)[CH3:2].P(Br)(Br)Br.C(N(CC)C(C)C)(C)C.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]1>C1(C)C=CC=CC=1.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2cc(CO)ccc2o1
Reactant: CCOC(=O)C1CCNCC1
Agent: BrP(Br)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCN(Cc2ccc3oc(CC)nc3c2)CC1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
To a stirred solution of 3.4 grams (0.019 mole) of (2-ethylbenzoxazol-5-yl)methanol in 25 mL of toluene was added 1.6 grams (0.006 mole) of phosphorous tribromide from a syringe. A precipitate formed immediately, and additional toluene was added to the reaction mixture to aid stirring. The reaction caused the reaction mixture temperature to rise to about 35° C. Upon completion of the addition, the reaction mixture stirred for an additional 20 minutes. The reaction mixture was then concentrated under reduced pressure to a residual solid. The solid was dissolved in 30 mL of dimethyl sulfoxide and, with stirring, 3.7 grams (0.029 mole) of N,N-diisopropylethylamine and 3.1 grams (0.019 mole) of ethyl piperidin-4-ylcarboxylate were added simultaneously from syringes. The resultant reaction caused the reaction mixture temperature to rise to about 40° C. The reaction mixture was allowed to cool to ambient temperature as it stirred for about 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate and then with diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium bicarbonate, and then with an aqueous solution saturated with sodium chloride. The organic layer was concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with ethyl acetate as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.1 grams of ethyl N-(2-ethylbenzoxazol-5-ylmethyl)piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.