Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.N.[OH-].[Na+].C(OC(C)C)(C)C.O=C(C)C(=S)[NH2:37]>N.CCOC(C)=O>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:37])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC(=O)C(N)=S
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(=S)N1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(N)=N1
Temperature: 74 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 19 Step 3, 22.7 g, 57.7 mmol) and ammonia (7 M in MeOH, 180 mL, 1.26 mol) was put in a pressure reactor and heated to 74° C. overnight. The residue was allowed to reach r.t. and the mixture was concentrated. The residue was partitioned between 2 M citric acid (400 mL) and EtOAc (400 mL). Any insoluble material was filtered off and was determined to be unreacted starting material. The organic phase (org 1) was concentrated in vacuo to give additional unreacted starting material. To the aqueous phase was EtOAc (300 mL) added and then 50% NaOH was added until pH ˜12, and the mixture was stirred for 10 min. The resulting organic phase (org 2) was saved. The residue from org 1, and the solid filtered off were combined and suspended in ammonia (7 M in MeOH, 180 mL, 1.26 mmol) and put in a pressure reactor and heated 100° C. overnight. The obtained solution was concentrated in vacuo. The residue was partitioned between 2 M citric acid (300 mL) and EtOAc (300 mL). To the aqueous phase was EtOAc (300 mL) added and then 50% NaOH was added until pH ˜12, and the mixture was stirred for 10 min. The organic phase was combined with org 2 from above. Activated charcoal was added to the organic phase and the mixture was stirred for 30 min before it was filtered through diatomaceous earth. The organic phase was concentrated and dried in vacuo overnight to give a solid. To the solid was diisopropyl ether (125 mL) added and the mixture was refluxed overnight. The mixture was allowed to reach r.t. and the solid was filtered off to give the title compound (equivalent to Example 19 Isomeric Mixture 2 above) (15 g, 69% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 0.93 (m, 1 H) 1.1-1.25 (m, 2 H) 1.35-1.45 (m, 3 H) 1.81 (br. d, 2 H) 2.16 (s, 3 H) 2.87-3.03 (m, 3 H) 3.18 (s, 3 H) 6.59 (br. s., 2 H), 6.64 (d, 1 H), 7.25 (d, 1 H), 7.34 (dd, 1 H); ES+) m/z 376 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[C:19](OCC)(=O)C.O>CO.S(=O)(=O)(O)O>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Commercially available 4-bromo-3-nitro-benzoic acid (1.17 g, 4.76 mmol) was dissolved in methanol (5 mL) containing five drops of concentrated sulfuric acid. The mixture was heated in air at 90° C. for six hours and more MeOH (7 mL) followed by concentrated sulfuric acid (0.6 mL) was added. Heating was continued another 24 hours. Extractive work up (ethyl acetate-water) followed by drying over MgSO4, filtered and concentrated under vacuum giving the title compound in quantitative yield.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl>[CH3:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)=[CH:14][CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: COCc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCc1ccc(-c2ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nn23)cc1
Temperature: 90 °C
Yield: 94.4 %

Procedure:
(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (85 mg, 0.22 mmol), 4-Methoxymethylphenylboronic acid (72.8 mg, 0.439 mmol), Triphenylphosphine (16 mg, 0.062 mmol) and Palladium Acetate (4.9 mg, 0.022 mmol) were placed in a vial and purged with vac/N2. N,N-Dimethylformamide (4.0 mL, 52 mmol), 1,4-Dioxane (2.0 mL, 26 mmol) and 2.00 M of Sodium carbonate in Water (1.02 mL, 2.04 mmol) were added and the mixture again purged (vac/N2) before being heated to 90° C. for 3 h. The mixture was cooled, diluted with EtOAc (10 mL) and ext. w/3M HCl (3×10 mL). The aq. extr. was washed with EtOAc (10 mL), then basified with NaOH (15% w/w), giving a slurry. The slurry was extr. with DCM (3×10 mL) and the org. extr. washed with brine (10 mL), dried over sodium sulfate and conc. in vacuo to give [7-(4-Methoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (89 mg, 94%). LCMS (HPLC): 0.87 min, m/z=429 (M+H); 1H-NMR (CDCl3): 8.67 (s, 1H), 8.14 (d, 2H, J=8.2 Hz), 7.55 (d, 2H, J=8.9 Hz), 7.45 (d, 2H, J=8.2 Hz), 7.00 (d, 1H, J=4.7 Hz), 6.95 (d, 2H, J=8.9 Hz), 6.81 (d, 1H, J=4.7 Hz), 6.64 (s, 1H), 4.55 (s, 2H), 3.45 (s, 3H), 3.20 (m, 4H), 2.61 (m, 4H), 2.37 (s, 3H).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.[C:27](#[N:29])[CH3:28].[NH2-].[Na+]>C1C=CC=CC=1>[OH:8][C:7]([C:4]1[CH:3]=[CH:2][C:1]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:6][CH:5]=1)([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:28][C:27]#[N:29]
Reactant: CC#N
Reactant: O=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CCC(O)(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
Di-4-biphenylyl ketone was reacted with acetonitrile in benzene in the presence of sodamide by the method of Lettre and Wick (Annalen, 1957, 603, 194) to give 3-hydroxy-3, 3-di(4-biphenylyl) propionitrile, m.p. 168°-170° C, after recrystallisation from benzene. The nitrile (8.0 g.) dissolved in a mixture of tetrahydrofuran (80 ml.) and ether (80 ml.) was added over 30 minutes at room temperature under nitrogen to a stirred suspension of lithium aluminium hydride (2.88 g.) in ether (75 ml.). After stirring a further hour the mixture was decomposed by addition of water (2.8 ml.) and aqueous N sodium hydroxide (12 ml.) After filtration, the organic layer was separated and evaporated to give a solid which recrystallised from benzene/light petroleum (b.p. 80°-100° C), gave 1,1-di(4-biphenylyl)-3-aminopropan-1-ol, prisms, m.p. 176°-8° C,λmax (ethanol) = 260 nm. The carbinol (6.5 g.) boiled under reflux for 1 hour with glacial acetic acid (40 ml.) and concentrated hydrochloric acid (10 ml.) gave 1, 1-di-(4-biphenylyl)-3-aminoprop-1-ene hydrochloride, needles from n-propanol, m.p. 231°-232° C. The base, from ethanol, had m.p. 127°-8° C, λmax (ethanol) = 274 nm.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH3:2].[NH4+:23].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:23])[C:8]=2[N:18]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NC(C)C
Reaction time: 0.5 h

Procedure:
A solution of N-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (0.93 g, 3.10 mmol) in 25 mL of CH2Cl2 was treated with 15 mL of concentrated NH4OH solution. To the rapidly stirred solution was added p-toluenesulfonyl chloride (620 mg, 3.25 mmol). After stirring for 30 min, the reaction was treated with CH2Cl2 (20 mL) and H2O (15 mL). The layers were separated and the organic portion was washed with 2% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give a tan solid. Chromatography (SiO2, 5% MeOH/CHCl3) gave 2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (368 mg) as a tan solid. mp 162–164° C.; 1H NMR (300 MHz, CDCl3) δ 8.60 (dd, J=8.2, 1.1 Hz, 1H), 7.77 (dd, J=8.4, 0.7 Hz, 1H), 7.54–7.47 (m, 1H), 7.33–7.54 (m, 1H), 5.55 (d, J=3.2 Hz, 1H), 5.41 (s, 2H), 4.89 (s, 2H), 3.73–3.60 (m, 3H), 1.26 (t, J=7.0 Hz, 3H); 1.15 (d, J=6.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 151.1, 148.7, 145.0, 127.7, 126.6, 123.9, 121.9, 121.3, 115.4, 66.8, 65.7, 52.5, 20.6, 15.1; MS m/z 300 (M+H)+; Anal. Calcd for C16H21N5O.0.48 H2O: C, 62.39; H, 7.19; N, 22.74; Found: C, 62.38, H, 6.90; N, 22.79.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH2:7][CH:8]=[CH2:9])C=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C1(C)C=CC=CC=1>[CH3:15][N:14]1[C:10]([CH:6]2[CH2:7][CH2:8][CH:9]=[CH:1][O:4][CH2:5]2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[N:13]1
Reactant: C=CCOCC(CC=C)c1c([N+](=O)[O-])cnn1C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1ncc([N+](=O)[O-])c1C1CCC=COC1
Temperature: 120 °C
Yield: 28.4 %

Procedure:
A solution of 1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium, “Grubb's catalyst 2nd generation”, CAS Reg. No. 246047-72-3, Sigma-Aldrich Product No. 569747, U.S. Pat. No. 6,111,121, U.S. Pat. No. 7,329,758 (375 mg, 0.42 mmol) in toluene (15 ml) was added to a solution of 5-[1-(allyloxymethyl)but-3-enyl]-1-methyl-4-nitro-pyrazole (527 mg, 2.10 mmol) in toluene (115 mL). The resulting solution was heated at reflux (120° C.) for 2.5 h. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was purified via silica gel chromatography (0-100% EtOAc/heptane) to afford 1-methyl-4-nitro-5-(2,3,4,5-tetrahydrooxepin-3-yl)pyrazole (133 mg, 30%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[N:7]=[C:8](Cl)[C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[S:12][C:10]=2[N:11]=1.Cl.[CH:22]1([NH:25][CH3:26])[CH2:24][CH2:23]1>CO>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[N:7]=[C:8]([N:25]([CH:22]2[CH2:24][CH2:23]2)[CH3:26])[C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[S:12][C:10]=2[N:11]=1
Reactant: COC(=O)CCc1nc(Cl)c2c3c(sc2n1)CCCC3
Reactant: CNC1CC1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Reaction time: 10 h
Yield: 45.2 %

Procedure:
The TEA (0.6 g, 0.0064 mol) was added dropwise at 10° C. to a mixture of 3-(4-chloro-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid methyl ester (1 g, 0.0032 mol) and cyclopropyl methyl amine hydrochloride (0.35 g, 0.0032 mol) in methanol (20 ml). The resulting mixture was stirred at R.T for 10 hrs. Methanol was removed and the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4, concentrated and subjected to column purification on 60-120 silica using ethyl acetate (50%) in hexane to give 0.5 g (43%) of 3-[4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl]-propionic acid methyl ester. 1H NMR (400 MHz, DMSO) δ ppm=0.35 (m, 2H), 0.72 (m, 2H), 1.69 (m, 2H), 1.85 (m, 2H), 2.77 (q, 4H), 2.86 (q, 2H), 2.9 (m, 1H), 2.97 (s, 3H) 3.02 (t, 2H), 3.56 (s, 3H). LC-MS: [M+H]=345.8.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][O:30][CH3:31]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:28][CH2:29][O:30][CH3:31])[CH2:26][CH2:25][O:24][CH3:23])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Reactant: COCCNCCOC
Product: COCCN(CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and bis(2-methoxyethyl)amine were converted to yield-{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-bis-(2-methoxy-ethyl)-amine as colorless oil, MS: 432 (MH+).
Reaction SMILES: [C:1]([C:4]1[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[S:6][N:5]=1)([OH:3])=[O:2].[OH-].[Na+:17]>CO.O>[C:1]([C:4]1[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[S:6][N:5]=1)([O-:3])=[O:2].[Na+:17]
Reactant: O=C(O)c1nsc2nc3ccccc3n12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])c1nsc2nc3ccccc3n12
Reaction time: 4 h
Yield: 95 %

Procedure:
To a suspension of 3-carboxy-1,2,4-thiadiazolo[4,5-a]benzimidazole (10.00 g, 45.62 mmol) in methanol (150 ml) and water (100 ml), 1M NaOH (45.6 ml) was added over a period of 1 h. After 4 h, the solution turned clear and the methanol was removed under reduced pressure. The aqueous solution was extracted with chloroform, the aqueous phase was freeze-dried to give the title compound (10.4 g, 95%) as a white solid: mp 225°-227° C.; 1H NMR (DMSO-d6) δ7.68 (d, 1H), 7.05 (d, 1H), 6.95 (t, 1H), 6.80 (t, 1H) ppm; 13C NMR (DMSO-d6) δ167.20, 161.76, 149.68, 148.84, 129.52, 126.23, 122.74, 118.37, 116.06 ppm; IR (KBr) ν3395, 3243, 1663, 1641, 1522, 1443, 1334, 827, 729 cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:16][NH2:17])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:18]1[C:27]2[C:22](=[C:23]([C:28](=O)[CH3:29])[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1>ClCCCl.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:16]/[N:17]=[C:28](/[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:22]=2[CH:21]=[CH:20][N:19]=[CH:18]3)\[CH3:29])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cccc2cnccc12
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)NN)cc1
Solvent: O
Solvent: ClCCCl
Product: C/C(=N\NC(=O)C1CC1c1ccc(C(C)(C)C)cc1)c1cccc2cnccc12
Yield: 45.2 %

Procedure:
A solution of 2-(4-tert-butylphenyl)cyclopropanecarbohydrazide (200 mg, 0.86 mmol) and 1-(isoquinolin-5-yl)ethanone (147 mg, 0.86 mmol) in 1,2-dichloroethane (10 mL) was stirred at room temperature for 2 h. The reaction mixture was then diluted with water (5 mL) and the organic layer was separated, washed brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified via silica gel column chromatography to afford (E)-2-(4-tert-butylphenyl)-N′-(1-(isoquinolin-5-yl)ethylidene)cyclopropanecarbohydrazide (150 mg, 45%) as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([C:12]([OH:14])=O)[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(Cl)(=O)C(Cl)=O.O.[NH3:22].C1COCC1>CN(C=O)C.O>[O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([C:12]([NH2:22])=[O:14])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: N
Reactant: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 g of 4-oxoadamantane-1-carboxylic acid (1) was dissolved in 300 mL of MC and to the resulting solution was slowly added dropwise 30 mL of oxalic chloride. Then, five drops of DMF were added and the resulting mixture was stirred at room temperature for two hours, distilled under a reduced pressure, and then vacuum-dried. The compound as vacuum-dried was dissolved in 150 mL of anhydrous THF and the resulting solution was added dropwise to a solution prepared by mixing 60 mL of ammonia water and 150 mL of THF. This reaction was extremely exothermic and thus the reactor cooled with iced water. After being stirred for 30 minutes, solids in the reaction product were filtered off by using MC, and the organic solution being collected was dried over MgSO4 and then filtered and dried under a reduced pressure. The resulting product was recrystallized with a solution of MeOH and ether to provide 43 g of 4-oxoadamantane-1-carboxamide (2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[C:19]1([NH:25][CH2:26][CH:27]([NH2:29])[CH3:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:29][CH:27]([CH3:28])[CH2:26][NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CC(N)CNc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CC(CNc1ccccc1)Nc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 1-phenylamino-2-amino-propane hydrochloride and DBU in DME. ES-MS m/e (%): 335 (M+H+, 100).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([O:35][CH2:36][CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:16](OC)=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([O:35][CH2:36][CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:30])[CH3:29])[CH2:16][OH:17])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(OCCCO[Si](C)(C)C(C)(C)C)c(OCCCO[Si](C)(C)C(C)(C)C)c(OCCCO[Si](C)(C)C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCOc1cc(CO)cc(OCCCO[Si](C)(C)C(C)(C)C)c1OCCCO[Si](C)(C)C(C)(C)C
Yield: 86.9 %

Procedure:
Ester 10 (13.0 g, 18.5 mmol) and LiAlH4 (0.77 g, 20 mmol) in anhydrous THF (100 mL) were stirred at 0° C. for 1 hour. The reaction was quenched by the slow addition of H2O (20 mL). The reaction mixture was concentrated to approximately half volume and was then partitioned between EtOAc (250 mL) and water (500 mL). The aqueous phase was extracted with additional EtOAc (2×100 mL). The combined organic layers were dried over MgSO4 and concentrated to yield 10.82 g (87%) of 11 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 6.56 (s, 2H), 4.58 (d, 2H, J=4.5 Hz), 3.99-4.07 (m, 6H), 3.76-3.82 (m, 6H), 1.98 (quint, 4H, J=6.0 Hz), 1.91 (quint, 2H, J=6.0 Hz), 0.87 (s, 18H), 0.86 (s, 9H), 0.03 (s, 12H), 0.02 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 152.9, 136.9, 136.3, 104.9, 70.3, 65.4, 65.2, 60.3, 59.6, 33.5, 32.5, 25.8, 18.2, 5.4, 5.5; IR (film, NaCl) 3435 cm−1 (broad); High Resolution MS (electrospray), m/z 695.4178 (Calcd for C34H68O7Si3+Na+: 695.4171).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:28]2[CH2:29][CH2:30][C:25]([F:31])([F:24])[CH2:26][CH2:27]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: FC1(F)CCNCC1
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CCOC(=O)c1c(N2CCC(F)(F)CC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 11 step C from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B) and 4,4-difluoro-piperidine. Pale yellow solid (110 mg, 44%). LC-MS: 431 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].CC([O-])=O.[Na+]>CCO>[NH2:23][C:21]1[S:22][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)(=[O:13])=[O:12])=[CH:7][CH:6]=2)[N:20]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1ccc(S(=O)(=O)NC2CCCC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2ccc(S(=O)(=O)NC3CCCC3)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(2-Bromo-acetyl)-N-cyclopentyl-benzenesulfonamide (150 mg, 0.43 mmol) was combined with thiourea (33 mg, 0.43 mmol) in 7 ml of dry EtOH. To this solution was added NaOAc (53 mg, 0.65 mmol). Reaction mixture was stirred at room temperature for 4 hours. Reaction mixture was evaporated to dryness and used in the next step without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2].C(=O)(O)[O-:18].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].S([O-])(O)=O.[Na+]>CC(C)=O.C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]2[C:6]=1[C:7](=[O:18])[CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(F)c(C)c2c1CCCC2
Reactant: O=C([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(F)c(C)c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
In acetone, 5.0 g of 5-acetylamino-7-fluoro-8 -methyl-1,2,3,4-tetrahydronaphthalene were suspended, followed by the addition of 2.3 g of sodium bicarbonate. To the resulting mixture, 13.9 g of potassium permanganate were added in portions over 3.5 hours at an internal temperature of 10° to 15° C. and the mixture was stirred at room temperature for one hour. To the resulting mixture, 0.8 g of potassium permanganate was added further, followed by stirring for 1.5 hours. After a 5% aqueous solution of sodium hydrogensulfite was added in a small amount and the complete disappearance of potassium permanganate was confirmed, manganese dioxide so precipitated was filtered out. The manganese dioxide was washed thoroughly with chloroform and the filtrate was removed under reduced pressure. The residue so obtained was dissolved in chloroform. The resulting solution was washed three times with a saturated aqueous solution of sodium bicarbonate and dried over potassium carbonate. The solvent was evaporated under reduced pressure. The residue so obtained was recrystallized from chloroform-diethyl ether, whereby 2.6 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[N:19]=[C:18]([F:20])[C:17]([I:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13]([CH3:15])C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1CN)[CH3:23]>C1COCC1>[F:1][C:2]1[N:19]=[C:18]([F:20])[C:17]([I:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:15][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[CH2:22][CH3:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(I)c(F)nc1F
Reactant: CCN1CCC[C@H]1CN
Solvent: C1CCOC1
Product: CCOC(=O)C(=CNC[C@@H]1CCCN1CC)C(=O)c1cc(I)c(F)nc1F
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 66.3 %

Procedure:
Ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-(dimethylamino)acrylate (Intermediate 37, 0.500 g, 1.10 mmol) was taken up THF (40 mL) and cooled to 0° C. for 10 min and then (S)-(1-ethylpyrrolidin-2-yl)methanamine (0.153 mL, 1.10 mmol) was added and stirred at room temperature for 2 min. The reaction mixture was quenched with sat NH4Cl diluted with EtOAc and separated, dried, and solvent removed. The residue was purified by a 0-5% gradient on the ISCO of DCM/Methanol to give (S)-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-((1-ethylpyrrolidin-2-yl)methylamino)acrylate (0.360 g, 67%) as a red oil.