Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][NH2:14])[O:9][C:8]=2[CH:15]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:31])[CH:26]=[CH:27][O:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25](=[O:31])[CH:26]=[CH:27][O:28]4)=[CH:23][CH:22]=3)[O:9][C:8]=2[CH:15]=1
Reactant: O=c1ccoc2cc(OCCCBr)ccc12
Reactant: COc1ccc2c(c1)OC(CN)CO2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)OC(CNCCCOc1ccc3c(=O)ccoc3c1)CO2
Temperature: 80 °C
Yield: 4.4 %

Procedure:
2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine hydrochloride (4.0 g, 17 mmole), 7-(3-bromopropoxy)chromen-4-one (4.9 g, 17 mmole) and diisopropylethylamine (15.1 ml, 87 mmole) were combined in 150 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. The residue was chromatographed on a silica gel column using first dichloromethane and then 5% methanolic dichloromethane as eluents. The fractions containing material with Rf=0.59 on silica gel tlc (chloroform/methanol/ammonia=95/5/1) were combined, concentrated, and the residue was dissolved in 50% methanol/dichloromethane. The mixture was then treated with 4N isopropanolic HCl until the solution was 3 in pH and crystallized by triturating with ether. Two further recrystallizations gave 0.3 g of title compound as a yellow solid hydrochloride, quarter hydrate, m.p. 155°-157° C.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:13][C:12]([C:31]2[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([F:39])[CH:32]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:32]=[C:33]([F:39])[C:34]([OH:38])=[C:35]([F:37])[CH:36]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(F)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(F)c4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[3-(cyclopropanecarbonyl)-6-(3,5-difluoro-4-hydroxyphenyl)quinolin-4-ylamino]cyclohexylcarbamate (26.2 mg, 0.049 mmol) was reacted with TFA (2 mL) to afford the desired product (17 mg, 79%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.14 (s, 1H), 8.36 (s, 1H), 8.03 (d, J=9.5 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.35 (d, J=9.6 Hz, 2H), 4.16 (s, 1H), 3.07 (s, 1H), 2.85 (s, 1H), 2.36 (d, J=10.7 Hz, 2H), 2.18 (d, J=14.1 Hz, 2H), 1.75-1.51 (m, 4H), 1.20 (s, 2H), 1.11 (s, 2H); ESI MS m/z 438 [C25H25F2N3O2+H]+; HPLC 98.5% (AUC), tR=8.70 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:10])=[O:9].Cl.C(O[CH:15](OCC)[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])[CH2:20][CH2:19]1)C>C(O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH:15]3[NH:10][C:8](=[O:9])[C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=4)[NH:1]3)[CH2:19][CH2:20]2)=[O:25])=[CH:31][CH:30]=1
Reactant: CCOC(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)OCC
Reactant: NC(=O)c1ccccc1N
Agent: Cl
Solvent: CCO
Product: O=C1NC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)Nc2ccccc21
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of 9 parts of 2-aminobenzenecarboxamide, 12 parts of concentrated hydrochloric acid and 120 parts of absolute ethanol is stirred and refluxed for 2 hours. Then there are added 3.6 parts of [1-(3,3-diethoxypropyl)-4-piperidinyl](4-fluorophenyl)methanone and stirring at reflux is continued overnight. The reaction mixture is evaporated and the residue is stirred with water. The whole is alkalized with ammonia and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized twice from 4-methyl-2-pentanone, yielding 1.9 parts (19%) of 2-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-4(1H)-quinazolinone; mp. 153.4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[Te:11](Cl)([Cl:14])([Cl:13])[Cl:12]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Te:11]([Cl:14])([Cl:13])[Cl:12])[CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: Cl[Te](Cl)(Cl)Cl
Reactant: COc1ccccc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc([Te](Cl)(Cl)Cl)cc1OC
Reaction time: 0.5 h

Procedure:
1,2-Dimethoxybenzene (veratrole, 13.8 g=0.1 mole) and tellurium tetrachloride (26.9 g=0.1 mole) were heated in chloroform (120 ml) for 2 hours under reflux and with stirring. After 30 minutes yellow crystals started to precipitate. The product (25.2 g, 67.9% of theory) was collected by filtration and dried in a vacuum oven, m.p. 162°-163° C. (dec. with gas evolution). The mass spectra were in agreement with that of the structural formula.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CN(C)C=O>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc([N+](=O)[O-])c1F
Temperature: 80 °C
Yield: 98.1 %

Procedure:
2-Fluoro-3-nitro-benzoic acid (16, 0.497 g, 2.68 mmol) is combined with thionyl chloride (3 mL, 40.0 mmol) and N,N-dimethylformamide (20 μL, 0.2 mmol) and the reaction is heated at 80° C. overnight. The reaction is concentrated under vacuum, suspended in toluene and concentrated under vacuum twice, and dried to provide the desired compound as a white solid (17, 0.535 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si](CC)(CC)CC)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[F:15][C:12]([F:13])([F:14])[C:11]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:2]([CH3:1])=[CH:10]2)([OH:20])[C:16]([F:19])([F:18])[F:17]
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2CCc1ccccc1)(C(F)(F)F)C(F)(F)F
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1CCc1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 45.4 %

Procedure:
89 mg (ca. 0.17 mmol) of the crude 2-methyl-1-phenethyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole obtained (example 55) were dissolved in 1 mL of toluene and treated with 92 mg (1.1 mmol) of MnO2 powder. The mixture was stirred at 80° C. for 48 hrs, filtrated and the solvent evaporated. The residue was dissolved in 1 mL of THF and treated with 0.08 mL of a 1M TBAF solution in THF. Stirring for 30 min, evaporation of the solvent and column chromagraphy on silica gel with n-heptane/EtOAc 3:1 yielded 31 mg (ca. 33%) of 1,1,1,3,3,3-hexafluoro-2-(2-methyl-1-phenethyl-1H-indol-5-yl)-propan-2-ol, light brown oil, MS: 400 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]([NH:15][CH3:16])=[CH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]1=[O:19].[CH3:20][CH:21]([C:25]([OH:27])=O)[C:22]([OH:24])=O>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:16])[C:25](=[O:27])[C:21]([CH3:20])=[C:22]([OH:24])[C:13]=2[C:12](=[O:17])[N:11]([CH3:18])[C:10]1=[O:19]
Reactant: CC(C(=O)O)C(=O)O
Reactant: CNc1cc(=O)n(C)c(=O)n1-c1ccc(I)cc1F
Solvent: CC(=O)OC(C)=O
Product: Cc1c(O)c2c(=O)n(C)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Temperature: 95 °C
Yield: 37.2 %

Procedure:
To a 6:5 mixture (59.6 g) of 1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine-2,4-dione 67 and 3-(2-fluoro-4-iodophenyl)-1-methyl-6-methylamino-1H-pyrimidine-2,4-dione 68 obtained in Step 4 and 2-methyl-malonic acid 54 (20.7 g) was added acetic anhydride (180 ml), and the mixture was stirred with heating at 95° C. for 1 hr. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. Tetrahydrofuran (350 ml) was added to the residue, and the mixture was stirred with heating under reflux for 1 hr. After allowing to cool to room temperature, the crystals were filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (chloroform:tetrahydrofuran=18:1). Toluene (150 ml) was added to the obtained solid, and the mixture was stirred with heating under reflux for 30 min. After allowing to return to room temperature, the crystals were collected by filtration and dried to give 1-(2-fluoro-4-iodophenyl)-5-hydroxy-3,6,8-trimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 69 (27.0 g, yield 37%) as colorless crystals.
Reaction SMILES: [N:1]([Sn](CCCC)(CCCC)CCCC)=[N+:2]=[N-:3].[F:17][C:18]([F:52])([F:51])[C:19]1[CH:20]=[C:21]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:22][N:23]([C:42]#[N:43])[CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:26]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:25]1=2.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[F:50][C:47]([F:48])([F:49])[C:45]1[CH:44]=[C:21]([CH:20]=[C:19]([C:18]([F:17])([F:51])[F:52])[CH:46]=1)[CH2:22][N:23]([C:42]1[NH:3][N:2]=[N:1][N:43]=1)[CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:26]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:25]1=2
Reactant: CC(C)OC(=O)N1CCCC(N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Add azidotributyltin (0.19 mL, 0.68 mmol) to a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-cyano-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (180 mg, 0.34 mmol) in toluene (3.6 mL). Stir the mixture at 80° C. overnight. Cool down the mixture to room temperature; add ethyl acetate and 1N HCl (8.2 mL) and stir at room temperature for 1 h. Separate the layers, wash the organic phase with saturated KF, then with brine, dry over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with dichloromethane/methanol, and then by reverse phase purification to provide 198 mg (quantitative) of the title compound. MS (ES−): 575 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1>[Ni].C(O)C.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(F)cc2[nH]1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4ccc(F)cc4[nH]3)cccc21
Yield: 97.1 %

Procedure:
Carry out the procedure as in Example 6, starting from 1.7 g of 4-(6-fluoro-1H-benzimidazol-2-yl)-fluoren-9-one oxime (Z,E), obtained in Example 70, and 6 mg of Raney Nickel in 90 ml of ethanol and 90 ml of tetrahydrofuran for 4 hours at 60° C. under a hydrogen pressure of 1 bar. After purification by making a paste in diisopropyl ether, we obtain 1.58 g of 4-(6-fluoro-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a beige powder with the following characteristics:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:14][OH:15])=[CH:9][C:8]=1[O:16][CH3:17])(=[O:5])=[O:4].ClN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]([C:38]([F:41])([F:40])[F:39])=[CH2:37])[CH:32]=[C:33]([Cl:35])[CH:34]=1.C(N(CC)CC)C>CN(C)C=O>[F:19][C:2]([F:18])([F:1])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:37][C:36]([C:31]3[CH:32]=[C:33]([Cl:35])[CH:34]=[C:29]([Cl:28])[CH:30]=3)([C:38]([F:39])([F:41])[F:40])[O:15][N:14]=2)=[CH:9][C:8]=1[O:16][CH3:17])(=[O:4])=[O:5]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: COc1cc(C=NO)ccc1OS(=O)(=O)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
In a solution of 2.0 g of 4-hydroxyiminomethyl-2-methoxyphenyl trifluoromethane sulfonate in 30 ml of N,N-dimethylformamide, 0.9 g of N-chlorosuccinic acid imide was added, and stirred at 40 to 50° C. for 30 minutes. Then, the reaction mixture was left and cooled to room temperature, 1.5 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 3 and 0.7 g of triethylamine were added, and stirred at room temperature for 90 minutes. After the completion of the reaction, the reaction mixture was poured in 100 ml of ice water, extracted with ethyl acetate (50 ml×2), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:7), and 1.4 g of the aimed product was obtained as colorless resinous substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[N:7]=1.[C:15]1([CH:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C.[Cl-].[Na+]>CN(C)C=O>[C:33]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH:32][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=4)[N:7]=3)[CH2:25][CH2:24]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: COC(=O)c1nc2ccc(Cl)nn2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 80 °C
Yield: 29.6 %

Procedure:
0.92 g of methyl 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylate and 1.40 g of 4-(diphenylmethoxy)-1-piperidinepropanamine were suspended in 20 ml of N,N-dimethylformamide; 1.49 ml of N-ethyldiisopropylamine was added, followed by heating and refluxing at 80° C. for 15 hours. After cooling, ice water and sodium chloride were added, followed by extraction with ethyl acetate-tetrahydrofuran (1:2); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; the residue was recrystallized from ethanol-ethyl acetate (1:2) to yield 639 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH:22]1[CH2:25][CH:24]([C:26]#[N:27])[CH2:23]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:22]3[CH2:25][CH:24]([C:26]#[N:27])[CH2:23]3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: N#CC1CNC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 31.1 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), azetidine-3-carbonitrile (2.7 mg, 0.032 mmol), 4-methylmorpholine (4.93 mg, 0.049 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a semi-solid (3.7 mg, 30.6%). 1H NMR (400 MHz, CD3OD) δ 0.94 (t, J=6.32 Hz, 3 H) 1.07 (dd, J=18.19, 6.32 Hz, 3 H) 2.44-2.59 (m, 1 H) 3.47-3.79 (m, 1 H) 4.15-4.40 (m, 2 H) 4.57 (dt, J=9.73, 4.99 Hz, 1 H) 4.63-4.78 (m, 1 H) 4.84 (d, J=19.71 Hz, 1 H) 5.06-5.30 (m, 2 H) 7.82 (d, J=11.37 Hz, 1 H) 8.25 (d, J=5.56 Hz, 1 H). [M+H] calc'd for C18H18ClN5O2, 372; found, 372.4.
Reaction SMILES: [NH:1]([C:5]1[C:6]([F:13])=[CH:7][C:8]([CH3:12])=[C:9]([SH:11])[CH:10]=1)C(C)=O.[OH-].[K+].Cl>O>[NH2:1][C:5]1[C:6]([F:13])=[CH:7][C:8]([CH3:12])=[C:9]([SH:11])[CH:10]=1
Reactant: CC(=O)Nc1cc(S)c(C)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(F)c(N)cc1S

Procedure:
Crude 5-acetamino-4-fluoro-2-methyl-benzenethiol (280 g, 1.41 mol) was added to a 5% (w/w) solution of potassium hydroxide (250 g, 4.46 mol) in water and the mixture was refluxed for 5 hours. The resulting solution was adjusted to pH 7 with dilute hydrochloric acid and was then extracted with ethyl acetate. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to give 5-amino-4-fluoro-2-methyl-benzenethiol as a crude intermediate (160 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:5]=[CH:4][C:3]=1C#N.P(=O)(O)(O)O.[OH-].[NH4+]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnn(-c2cccc([N+](=O)[O-])c2)c1N
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccnn1-c1cccc([N+](=O)[O-])c1
Yield: 79.9 %

Procedure:
5-amino-1-(3′-nitrophenyl)-4-cyanopyrazole (559 mg, 2.44 mmol) and phosphoric acid (86%, 6 ml) were refluxed at 170° C. for 15 h. The reaction was cooled to room temperature and neutralized with ammonium hydroxide. The organics were extracted three times with diethyl ether (total 40 ml), washed with brine, and dried over magnesium sulfate. Removal of solvent gave 5-amino-1-(3′-nitrophenyl)-pyrazole as a yellow powder (398 mg, 80% yield).
Reaction SMILES: [C:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C[O:18][C:19](=O)[C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=O>>[C:1]1([C:13]2[C:14](=[O:15])[NH:16][C:19](=[O:18])[C:20]=2[C:22]2[C:30]3[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(F)ccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(F)ccc12

Procedure:
Beginning with 2-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acetamide and (6-Fluoro-1H-indol-3-yl)-oxo-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1([Cl:7])[CH2:4][CH:3]1[CH2:5][OH:6].[H-].[Na+].CS[C:12]1[N:13]([CH2:22][CH2:23][CH3:24])[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][S:18][C:16]=2[N:17]=1>O1CCCC1>[Cl:1][C:2]1([Cl:7])[CH2:4][CH:3]1[CH2:5][O:6][C:12]1[N:13]([CH2:22][CH2:23][CH3:24])[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][S:18][C:16]=2[N:17]=1
Reactant: OCC1CC1(Cl)Cl
Reactant: CCCn1c(SC)nc2sccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(OCC2CC2(Cl)Cl)nc2sccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
In a sulfonation flask, 2.8 g (0.02 mol) of 2,2-dichlorocyclopropanmethanol are added to 40 ml of absolute tetrahydrofurane and under stirring 0.6 g (0.015 mol) NaH-dispersion is carefully added. After stirring for 1 hour at room temperature, a solution of 2.4 g (0.01 mol) 2-methylsulfanyl-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one in 20 ml tetrahydrofurane was added within 2 minutes. After stirring for 4 hours at room temperature the solvent is removed in a water-jet vacuum and the residue is taken up in TBME and the mixture washed repeatedly with water. The TBME-phase is concentrated in the water-jet vacuum and subsequently the excess 2,2-dichlorocyclopropylmethanol destined in high vacuum. 3.0 g of 2-(2,2-dichloro-cyclopropylmethoxy)-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one are obtained in the form of a white powder having a melting point of 64-66° C.
Reaction SMILES: COC([CH:5]1[C:10]([O-:11])=[CH:9][C:8](=[O:12])[CH2:7][CH:6]1[C:13]([F:16])([F:15])[F:14])=O.[Na+].[OH-].[Na+].S(=O)(=O)(O)O>>[F:14][C:13]([F:15])([F:16])[CH:6]1[CH2:7][C:8](=[O:12])[CH2:9][C:10](=[O:11])[CH2:5]1
Reactant: COC(=O)C1C([O-])=CC(=O)CC1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CC(=O)CC(C(F)(F)F)C1
Temperature: 25 °C

Procedure:
Sodium 6-(Methoxycarbonyl)-3-oxo-5-(trifluoromethyl)cyclohex-1-enolate (1.0 eq) was dissolved in 1M NaOH (1.0 eq), and the mixture refluxed for 1 h. After cooling to room temperature, the mixture was acidified with 5 M sulfuric acid. The mixture was extracted with EtOAc. After washing with water, the organic layer was dried over magnesium sulfate, the solvent was removed under reduced pressure to give 5-(trifluoromethyl)cyclohexane-1,3-dione, which was used to the next step without further purification (98%). LC/MS (m/z): MH+=181.1, Rt=0.55 min.
Reaction SMILES: [CH3:1][Si:2]([N:5]=[C:6]=[O:7])([CH3:4])[CH3:3].[CH3:8][O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH3:29]>N12CCCN=C1CCCCC2.ClCCl>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH3:29])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([O:9][CH3:8])[C:6]([NH:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CONCCCCn1c(C)nc2c(N)nc3ccccc3c21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CON(CCCCn1c(C)nc2c(N)nc3ccccc3c21)C(=O)N[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Trimethylsilyl isocyanate (1.62 mL, 12.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7ene (one drop) were added to a solution of 1-[4-(methoxyamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (3.00 g, 10.0 mmol) in dichloromethane (100 mL). The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure to afford 4.1 g of crude N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-methoxy-N′-(trimethylsilyl)urea, which was used without purification in the next step.