Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:30])[C:4]([C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1)=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1.N1C(C)=CC(C)=CC=1C.Cl[C:41]([O:43][CH3:44])=[O:42].Cl>C1(C)C=CC=CC=1>[CH3:44][O:43][C:41](=[O:42])[N:30]=[C:3]([S:2][CH3:1])[C:4]([C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1)=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: COc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCOC2
Reactant: COC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 23.8 g of the crude product of 2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]thioacetimidic acid methyl ester in 100 ml of toluene there were added 32 ml of collidine and 15 ml of methyl chloroformate, and the mixture was stirred at 80° C. for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, 1N hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (12.98 g) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[C:33]([CH:34]=[O:35])=[C:32]([N:36]4[CH2:48][CH2:47][C:46]5[N:45]6[C:40]([CH2:41][CH2:42][CH2:43][CH2:44]6)=[CH:39][C:38]=5[C:37]4=[O:49])[N:31]=[CH:30][CH:29]=3)[CH:21]=2)=[N:17][CH:18]=1.[BH4-].[Na+]>CO>[CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:29]=[CH:30][N:31]=[C:32]([N:36]4[CH2:48][CH2:47][C:46]5[N:45]6[C:40]([CH2:41][CH2:42][CH2:43][CH2:44]6)=[CH:39][C:38]=5[C:37]4=[O:49])[C:33]=3[CH2:34][OH:35])[CH:21]=2)=[N:17][CH:18]=1
Reactant: CC1CN(C2COC2)C(C)CN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(N5CCc6c(cc7n6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a solution of 155b (80 mg, 0.12 mmol) at 0° C. in methanol (5 mL) was added sodium borohydride (12 mg, 0.36 mmol). The reaction mixture was stirred for 30 minutes. It was then quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 155 (32 mg, 40%). MS-ESI: [M+H]+ 665.3. 1H NMR (500 MHz, CDCl3) δ 8.68 (d, J=2.0 Hz, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.37-7.33 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 6.32 (s, 1H), 5.02 (d, J=13.0 Hz, 1H), 4.78-4.71 (m, 2H), 4.67-4.61 (m, 3H), 4.44-4.39 (m, 1H), 4.31-4.29 (m, 1H), 3.96-3.91 (m, 1H), 3.86-3.80 (m, 2H), 3.78-3.75 (m, 1H), 3.72 (s, 3H), 3.21-3.19 (m, 1H), 3.01-2.93 (m, 3H), 2.85-2.83 (m, 2H), 2.72 (d, J=10.0 Hz, 2H), 2.49-2.47 (m, 1H), 2.05-2.03 (m, 2H), 1.98-1.97
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13](N)[N:14](C(OC(C)(C)C)=O)[CH2:15][C@H:16]([OH:26])[C@@H:17]([NH2:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)[CH2:5][CH3:6])[CH3:3].C[N:36](C=O)C>O1CCOCC1>[ClH:1].[CH2:2]([N:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH2:36])[CH2:15][C@H:16]([OH:26])[C@@H:17]([NH2:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)[CH2:5][CH3:6])[CH3:3]
Reactant: CCN(CC)c1ccc(C(N)N(C[C@H](O)[C@@H](N)Cc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(CN(N)C[C@H](O)[C@@H](N)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
850 ml of a 4M solution of hydrogen chloride in dioxane is added to a solution of 57 g (124.8 mmol) of 1-[p-(N,N-diethylamino)phenyl]-4(S)-hydroxy-2-(tert-butyloxycarbonyl)-amino-5(S)-amino-6-phenyl-2-azahexane (Example 2d) in 200 ml of DMF and the whole is stirred at RT for 4 h. After that, the mixture is concentrated and treated firstly with dioxane and then with toluene with subsequent evaporation taking place in each case. The residue is triturated twice with dioxane and decanted off. The oily title compound which is obtained in this way is subjected to further processing without any additional purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][C@H:29]1[CH2:33][CH2:32][O:31][CH2:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][C@H:29]3[CH2:33][CH2:32][O:31][CH2:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCC[C@H]1CCOC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC[C@H]1CCOC1

Procedure:
Prepared similarly to Intermediate 215 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (3R)-3-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH:17](O)[CH3:18])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O:30][C:31](=[O:34])[CH2:32]Br)([CH3:29])([CH3:28])[CH3:27].[OH-:35].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:26]([O:30][C:31](=[O:34])[CH2:32][O:35][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[CH:12]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(O)Oc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 48 h

Procedure:
0.2 g of [(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethan-1-ol was suspended in 1.7 ml of toluene and 0.7 ml of tetrahydrofuran. 0.1 ml of bromoacetic acid-tert-butyl ester, 13 mg of tetrabutylammonium hydrogen sulfate, and 1.45 ml of 32% sodium hydroxide solution were added to it, and it was allowed to stir for 48 hours. Another 0.1 ml of bromoacetic acid-tert-butyl ester and 13 mg of tetrabutylammonium hydrogen sulfate were added, and the mixture was left for 48 hours in an ultrasound bath. Then, it was diluted with water and extracted three times with toluene. The combined organic phases were washed with water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: FC(F)(F)C(O)=O.Br.[NH2:9][C:10]1[N:11]([CH2:42][CH2:43][CH2:44][NH:45]C(=O)OC(C)(C)C)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([N:22](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[C:13]=2[N:41]=1>>[NH2:45][CH2:44][CH2:43][CH2:42][N:11]1[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:22])[C:13]=2[N:41]=[C:10]1[NH2:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3c3c2nc(N)n3CCCNC(=O)OC(C)(C)C)cc1
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: NCCCn1c(N)nc2c(N)nc3ccccc3c21
Temperature: 50 °C
Reaction time: 72 h
Yield: 20.1 %

Procedure:
Trifluoroacetic acid (28.15 mL, 365.5 mmol) was added to tert-butyl 3-{2-amino-4-[bis(4-methoxybenzyl)amino]-1H-imidazo[4,5-c]quinolin-1-yl}propylcarbamate hydrobromide (8.3 g), and the reaction was heated at 50° C. for four hours, allowed to cool to ambient temperature, and stirred at ambient temperature for three days. The volatiles were removed under reduced pressure. The residue was purified by automated flash chromagraphy (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0.3:4.8:95 to 2.5:47.5:50) to provide 630 mg of 1-(3-aminopropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][N:29]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(N3CCNCC3)cc1)nn2-c1c(F)cccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nccc2c1c(-c1ccc(N3CCN(S(C)(=O)=O)CC3)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-3-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (260 mg) and triethylamine (112 mg) in dichloromethane (5 mL) was added methanesulfonyl chloride (99.0 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and diluted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (240 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([CH:14]=O)[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.C([O-])(=O)C.[NH4+].[N+:21]([CH3:24])([O-:23])=[O:22]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([CH:14]=[CH:24][N+:21]([O-:23])=[O:22])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: COc1c(C=O)cc2c(c1OC)CCC2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1c(C=C[N+](=O)[O-])cc2c(c1OC)CCC2

Procedure:
In a 2 liter 3-necked flask fitted with a condenser and thermometer and magnetically stirred, 126.7 g (0.613 mole) of 4,5-dimethoxy-6-indanaldehyde, 29.3 g (0.380 mole) of ammonium acetate, 127 ml (2.82 mole) of nitromethane and 390 ml of acetic acid were heated at 112°C for 45 minutes. After cooling in the refrigerator and scratching with a glass rod the solution crystallized. After filtering and washing with cold acetic acid the product was dried under vacuum overnight and recrystallized from methanol yielding 104.4 g (68%) of 4,5-dimethoxy-6 -nitrovinylindane as yellow needles, m.p. 103.5°-104.5°C. Anal. Calcd. for C13H15NO4 : C, 62.64; H, 6.06; N, 5.62. Found: C, 62.45; H, 6.17; N, 5.84.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH-].[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[C:23]1([CH2:22][O:21][C:19]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:20])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
To a suspension of tryptophan (20.08 g; 98.32 mmol) in H2O, cooled to 0° C., was added 1N NaOH (98 mL; 98 mmol) and the solution became clear. Maintaining the temperature at 0° C., 1N NaOH (108 mL; 108 mmol) and benzyl chloroformate (CBZCl, commercial product) (15.38 mL; 107.7 mmol) were simultaneously dropped in the reaction mixture. After the addition the mixture was kept at 0° C. for 30 min and then allowed to rise to r. t. The reaction was monitored by HPLC (Chromatographic method of Example 3, A). After further 3 h the pH was corrected to 9.5 by addition of 1N NaOH and the mixture was washed with Et2O (200 mL). The aqueous layer was acidified to pH 2 using 2N HCl and the precipitate was filtered through a G3 septum, washed with cold water (2×200 mL) and dried over P2O5 under vacuum (2 kPa). N-[(Phenylmethoxy)carbonyl]-L-tryptophan (33.96 g) was obtained and used in the following step without further purification.
Reaction SMILES: O[CH:2]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CC(C)=O>[CH3:15][N:12]1[CH2:11][CH2:10][C:9]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:2][C:3]3[C:8]2=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13]1
Reactant: CN1CCC2(CC1)c1ccccc1C(O)c1ccccc12
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Product: CN1CCC2(CC1)c1ccccc1Cc1ccccc12
Temperature: 220 °C
Reaction time: 0.5 h

Procedure:
10-Hydroxy-1'-methyl-9,10-dihydroanthracene-9-spiro-4'-piperidine (whose preparation is described in Example 2) (1 g.) and aluminium isopropoxide (3.1 g.) are thoroughly mixed and heated to 220°C. When acetone ceases to distil off the reaction mixture is heated to 225°C. for 40 minutes and then allowed to cool. Concentrated hydrochloric acid (7 ml.) in water (10 ml.) is added and the mixture is stirred for 30 minutes, basified with 2N sodium hydroxide and extracted with ethyl acetate. The organic layer is dried (Na2SO4) and evaporated to give a gum which crystallises on trituration with ether and is recrystallised twice from ether-petroleum ether (b.p. 40°- 60°C.) to give 1'-methyl-9,10-dihydroanthracene-9-spiro-4'-piperidine m.p. 132°-134°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].CN(C)C=O.[CH:23]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24]1.C(O)(=O)C>>[CH:23]1([C:26]2[N:31]=[C:30]([C:32]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)O)C2)nc1N
Reactant: O=Cc1ccnc(C2CC2)n1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylic acid in N,N-dimethylformamide (49 mL, 12.25 mmol, 0.25M) was added a solution of 2-cyclopropylpyrimidine-4-carbaldehyde in N,N-dimethylformamide (49 mL, 12.25 mmol, 0.25M) followed by acetic acid (7.35 mL, 122.5 mmol). The reaction mixture was stirred at 60° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via HPLC to afford (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid.
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].Cl[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(Cl)Cl>[CH:16]([S:17]([O:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4])(=[O:19])=[O:18])=[CH2:15]
Reactant: O=S(=O)(Cl)CCCl
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CS(=O)(=O)ON1C(=O)C2C3C=CC(C3)C2C1=O
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
A suspension of 5.38 g (30.0 mmol) of N-hydroxy-5-norbornene-2,3-dicarboximide and CH2Cl2 (120 ml) is successively treated with 2-chloroethanesulfonyl chloride (6.3 ml, 60.0 mmol) at room temperature and triethylamine (12.5 ml, 90.0 mmol) at 0° C. Stirring is continued for 1.5 h at room temperature and the resulting reaction mixture is treated with 10% aqueous sodium carbonate solution (100 ml) and ethyl acetate (200 ml). The organic phase is washed with. water (100 ml), dried over Na2SO4, and concentrated. The residue is further dried under vacuum, providing 5.89 g of pure product as light-yellow solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 1.53 (d, 1H), 1.76-1.81 (m, 1H), 3.12 (s, 2H), 3.48 (s, 2H), 6.17 (s, 2H), 6.29 (d, 1H), 6.53 (d, 1H), 6.78 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:6]C(C)(C)[O:8][CH2:9][C:4]=2[CH:3]=1.Cl>C(O)C>[F:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([OH:6])=[C:4]([CH2:9][OH:8])[CH:3]=1
Reactant: CC1(C)OCc2cc(F)cc(OCc3ccccc3)c2O1
Agent: Cl
Solvent: CCO
Product: OCc1cc(F)cc(OCc2ccccc2)c1O
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
To 6-fluoro-2,2-dimethyl-8-[(phenylmethyl)oxy]-4H-1,3-benzodioxine (9.9 g, 34.3 mmol) was added ethanol (50 mL) and 4 N HCl (aq) (50 mL). The mixture began as a suspension but became homogeneous while stirring for 20 min at 85° C. After cooling to rt, the ethanol was removed in vacuo, and the resulting aqueous mixture was extracted twice with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. 4-Fluoro-2-(hydroxymethyl)-6-[(phenylmethyl)oxy]phenol was isolated as a orange oil in quantitative yield. 1H NMR (400 MHz, CDCl3): δ 7.42-7.36 (m, 5H), 6.66-6.62 (m, 2H), 5.08 (s, 2H), 4.70 (s, 2H), 4.37 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.[OH-].[Na+].[N:19]([O-])=[O:20].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[N:19]=[O:20]
Reactant: O=N[O-]
Reactant: Cn1c(=O)cc(N)n(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)c(N=O)c(N)n(-c2ccccc2)c1=O
Reaction time: 2 h
Yield: 99.3 %

Procedure:
The obtained 6-amino-3-methyl-1-phenyluracil (24 g, 0.11M) and NaOH (2.8 g, 70 mM) were dissolved in 110 ml of water. To the resulting solution was added dropwise an aqueous solution of sodium nitrite (9.5 g/80 ml). Acetic acid (13 ml) was then added dropwise at 0° C. and the mixture was brought to room temperature, followed by stirring for 2 hours. A precipitated solid product was obtained by filtration. The solid product was washed successively with water and methanol and dried to yield 6-amino-3-methyl-5-nitroso-1-phenyluracil (yield: 27 g, or 99% based on 6-amino-3-methyl-1-phenyluracil).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]5([CH2:27][O:28][CH3:29])[CH2:26][CH2:25][NH:24][CH2:23]5)=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl[CH2:31][C:32]([N:34]1[CH2:39][CH:38]=[C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:51]=[CH:50][C:49]([F:52])=[CH:48][N:47]=3)=[C:42]([F:53])[CH:41]=2)[CH2:36][CH2:35]1)=[O:33].C(N(CC)CC)C>CN(C)C=O>[CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]5([CH2:27][O:28][CH3:29])[CH2:26][CH2:25][N:24]([CH2:31][C:32]([N:34]6[CH2:35][CH:36]=[C:37]([C:40]7[CH:45]=[CH:44][C:43]([C:46]8[N:47]=[CH:48][C:49]([F:52])=[CH:50][N:51]=8)=[C:42]([F:53])[CH:41]=7)[CH2:38][CH2:39]6)=[O:33])[CH2:23]5)=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COCC1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C5CC5)c4)c3c2)CCNC1
Reactant: O=C(CCl)N1CC=C(c2ccc(-c3ncc(F)cn3)c(F)c2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C5CC5)c4)c3c2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncc(F)cn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxymethyl-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-yl)-1H-indazol-5-yl]-amide (26AB) (85 mg, 0.217 mmol, 1 equiv) and 2-Chloro-1-{4-[3-fluoro-4-(5-fluoro-pyrimidin-2-yl)-phenyl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone (23AB) (84 mg, 0.239 mmol, 1.1 equiv) were weighed out in a flask and dissolved in anhydrous N,N-dimethylformamide (5 mL). Triethyl amine (33 mg, 46 uL, 0.326 mmol, 1.5 equiv) was added to the reaction mixture and the reaction content was stirred at room temperature overnight.
Reaction SMILES: [Cl:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:8][C:9]([NH2:11])=[S:10]>>[ClH:1].[S:10]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:8]=[C:9]1[NH2:11]
Reactant: O=C1CCCC1Cl
Reactant: NC(N)=S
Product: Cl
Product: Nc1nc2c(s1)CCC2
Temperature: 80 °C

Procedure:
A mixture of 2-chlorocyclopentanone (5.00 g, 39.5 mmol) and thiourea (3.00 g, 39.5 mmol) was heated at 80° C. for 3-4 minutes. After cooling to room temperature, the mixture was triturated with ethanol and the solid was collected by filtration to afford the title compound. MS (ESI) m/z 141 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([CH3:18])=[N:4][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C:6]=1[CH3:7].C([Mg]Cl)(C)C.CN([CH:27]=[O:28])C>C1COCC1>[CH3:18][C:3]1[C:2]([CH:27]=[O:28])=[C:6]([CH3:7])[N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[N:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c(I)c2C)cc1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(C)c(C=O)c2C)cc1
Temperature: -73 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
In a reaction vessel under inert atmosphere, 4-iodo-3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole x53 (1.44 g, 3.8 mmol) is dissolved in dry THF (10 ml) and cooled down to −73° C. A 2M solution of isopropylmagnesiumchloride in THF (9.6 mmol, 4.8 ml) is added dropwise and the mixture is stirred at −73° C. for 1 h. Then 0.44 ml of DMF (5.7 mmol) are added and the solution stirred at room temperature overnight. DMF (1.9 mmol) is further added and stirring is continued for 16 h. The reaction mixture is quenched with a saturated solution of NH4Cl, extracted three times with CH2Cl2, the organic phase is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.88 g of crude 3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde x56, which is used in the next step without any further purification.
Reaction SMILES: [C:1](#[N:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[CH2:9]([NH2:12])[CH2:10][CH3:11]>>[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:8]([CH2:4][CH2:5][CH3:6])[CH2:1][CH2:2][CH2:3][CH2:11][CH2:10][C:9]#[N:12])#[N:7]
Reactant: CCCN
Reactant: N#CCCCCC#N
Product: CCCN(CCCCCC#N)CCCCCC#N

Procedure:
116.0 g of adiponitrile and 15.7 mL of propylamine, (4 to 1 ratio of dinitrile to primary amine) were charged to a 300 cc autoclave along with 2.8 grams of catalyst (5 wt. % Pd on alumina powder). After purging with nitrogen, the reaction was pressurized to 50 psig with hydrogen and heating was commenced. Hydrogen was continuously replenished. After the temperature reached 110° C., stirring was increased to 1000 rpm and the hydrogen pressure was increased to 500 psig. The temperature and pressure were maintained for 1.5 hours. The product mixture comprised of 39% bis(cyanopentyl)aminopropane and 36% unconverted adiponitrile.