Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH:7][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccc([N+](=O)[O-])c1)C(=O)OCC

Procedure:
The intermediate lower-alkyl 7-amino-1-R-1,4-dihydro-4-oxo-3-quinolinecarboxylates of formula II are prepared in several steps by convention procedures as follows: m-nitroaniline is reacted with diethyl ethoxymethylenemalonate to form diethyl m-nitroanilinomethylenemalonate which is cyclized by heating in an appropriate solvent such as Dowtherm® A (eutectic mixture of 26.5% diphenyl and 73.5% diphenyl ether) or mineral oil at about 250°-260° C. to produce lower-alkyl 1,4-dihydro-7-nitro-4-oxo-3-quinolinecarboxylate, which is then alkylated at the 1-position by reaction with an appropriate alkylating agent, e.g., methyl, ethyl or n-propyl halide, diethyl sulfate, triethyl phosphate, or the like, preferably in the presence of an inert solvent, e.g., dimethylformamide, and an appropriate acid-acceptor, e.g., anhydrous potassium carbonate, to produce lower-alkyl 1-R-1,4-dihydro-7-nitro-4-oxo-3-quinolinecarboxylate, catalytically hydrogenating the 7-nitro compound in the presence of an appropriate catalyst, e.g., palladium-on-charcoal, to produce the corresponding ethyl 7-amino-1-R-1,4-dihydro-4-oxo-3-quinolinecarboxylate (II).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1)=[O:36]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (800 mg, 1.80 mmol) produced in Example D5(i) in N,N-dimethylacetamide (15 mL) was added chloroacetyl chloride (356 μL, 4.50 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (60 mL), and the mixture was extracted with ethyl acetate (60 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→30/70), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (823 mg, 88%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[C:9]([F:13])=[CH:8][C:7]=1[Br:14])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN1C(=O)CCC1.O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:9]([F:13])=[CH:8][C:7]=1[Br:14])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCOC(=O)Cc1cc(O)c(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)cc1Br
Temperature: 100 °C
Yield: 76.8 %

Procedure:
To a solution of (2-bromo-4-fluoro-5-hydroxy-phenyl)-acetic acid ethyl ester (0.42 1 g, 1.52 mmol) in NMP (5 ml) was added cesium carbonate (0.644 g, 1.97 mmol), sodium iodide (0.228 g, 1.52 mmol) and 2-bromoethoxy tert-butyldimethylsilane (0.424 g, 1.97 mmol). The mixture was heated at 100° C. for two hours. After cooling to room temperature, water was added and the product was extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexanes:EtOAc/8:2) gave {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic acid ethyl ester (0.508 g, 77%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.S(=O)(=O)(O)O.[N-:17]=[N+]=[N-].[Na+].C(OCC)(=O)C>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:17][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(Br)ccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C1NCCc2cc(Br)ccc21

Procedure:
In benzene (71 ml), 5-bromoindanone (5.47 g) was suspended. The solution was added with concentrated sulfuric acid (14 ml) and the whole was vigorously stirred. Then, the solution was gradually added with sodium azide (2.52 g), followed by stirring at room temperature for 30 minutes. The resultant was added with ethyl acetate, washed with water and a saturated saline solution, and dried with magnesium sulfate. The solvent was distilled off.
Reaction SMILES: [O-2].[Mg+2:2].[OH-].[Mg+2].[OH-].[B:6]([OH:9])([OH:8])[OH:7]>O>[B:6]([O-:9])([O-:8])[O-:7].[Mg+2:2].[B:6]([O-:9])([O-:8])[O-:7].[Mg+2:2].[Mg+2:2]
Reactant: OB(O)O
Agent: [Mg+2]
Agent: [O-2]
Agent: [OH-]
Solvent: O
Product: [O-]B([O-])[O-]

Procedure:
first adding, under continuous agitation, a sufficient amount of a powdered magnesium oxide or magnesium hydroxide to an aqueous radioactive waste solution containing boric acid, the temperature of the water solution being 55-95 degrees C. to produce a magnesium borate derivative;
Reaction SMILES: [F-].[K+].[OH:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][C:21]4[N:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=4)[CH:16]=3)[O:11]2)[CH:7]=[CH:8][CH:9]=1.Cl[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][N:34]=1.Cl>CN(C=O)C>[N+:39]([C:36]1[CH:37]=[CH:38][C:33]([O:3][C:4]2[CH:5]=[C:6]([CH:10]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][C:21]5[N:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=5)[CH:16]=4)[O:11]3)[CH:7]=[CH:8][CH:9]=2)=[N:34][CH:35]=1)([O-:41])=[O:40]
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(Oc4ccc([N+](=O)[O-])cn4)c2)O3)nc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Potassium fluoride (42 mg) was added into a solution of N-{6-[2-(3-hydroxy-phenyl)chroman-6-yloxy]pyridin-3-yl}methanesulfonamide (100 mg) in dry DMF (1 ml). After stirring the resulting mixture at 120° C. for 30 minutes 2-chloro-5-nitropyridine (40 mg) was added. The reaction mixture was stirred for a further 30 minutes at 120° C. After cooling into room temperature 1 M HCl-solution was added and formed precipitate was filtered. N-(6-{2-[3-(5-Nitropyridin-2-yloxy)phenyl]-chroman-6-yloxy}pyridin-3-yl) methanesulfonamide was purified by column chromatography using 1:1 mixture of ethyl acetate and heptane as eluant. 1H NMR (300 MHz, d6-DMSO) δ: 9.64 (s, 1H), 9.04 (d, 1H, J 2.9 Hz), 8.63 (dd, 1H, J 2.9, 9.1 Hz), 7.98 (d, 1H, J 2.7 Hz), 7.66 (dd, 1H, J 2.7, 8.8 Hz), 7.52 (t, 1H, J 7.7 Hz), 7.39 (d, 1H, J 7.7 Hz), 7.31 (s, 1H), 7.27 (d, 1H, J 9.1 Hz), 7.22-7.19 (m, 1H), 6.96 (d, 1H, J 8.8 Hz), 6.89-6.85 (m, 3H), 5.17 (d, 1H, J 7.8 Hz), 2.97 (s, 3H), 2.98-2.92 (m, 1H), 2.76-2.69 (m, 1H) 2.28-2.19 (m, 1H), 2.02-1.97 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH2:22][O:23][CH3:24])([CH3:21])[CH2:19][OH:20])=[O:16])=[CH:8][C:7]=2[CH3:27])#[CH:2].I[CH3:29].[H-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH2:19][O:20][CH3:29])([CH3:21])[CH2:22][O:23][CH3:24])=[O:16])=[CH:8][C:7]=2[CH3:27])#[CH:2]
Reactant: CI
Reactant: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(CO)COC)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(COC)COC)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (120 mg) in dry THF (7 ml) NaH (19 mg, 60% in oil) was added at room temperature under a nitrogen atmosphere. After 30 minute iodomethane (30 □l) was added to the reaction mixture. After stirring during 5 h one equivalent of NaH and one equivalent of iodomethane were added. The mixture was stirred overnight at room temperature, then quenched with water and diluted with ethyl acetate. The water phase was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography (cyclohexane/ethyl acetate/dichloromethane, 1:1:1) to give 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-methoxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (46 mg) as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[C:4]([C:23]([OH:25])=O)[CH:3]=1.S(Cl)([Cl:28])=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[OH:1][C:2]1[C:7]2[O:8][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[C:4]([C:23]([Cl:28])=[O:25])[CH:3]=1
Reactant: O=C(O)c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cl)c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 70 °C
Reaction time: 6 h

Procedure:
7-Hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid (334 mg, 1 mmol) was dissolved in chloroform (5 ml). One drop of triethyl amine was added. At 45 to 50° C. thionylchloride (0.33 ml, 4.5 mmol) was added within 30 minutes. The solution was than stirred for 6 hours at 70° C. The exccess thionyl chloride was removed by evaporation. The crude 7-hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl chloride was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:27])([F:38])[F:39])[CH:30]=2)=[O:37])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 mL) and 3-(trifluoromethyl)phenyl isocyanate (0.017 mL, 0.12 mmol) was added. The solution was stirred at room temperature for 1.5 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2:3 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.3, 161.1 (dd), 157.9 (dd), 155.0, 151.3, 141.5, 141.2, 138.1, 136.2, 135.0, 132.9, 132.8, 132.2 (q), 130.7, 128.8, 127.5 (dd), 126.0 (dd), 125.6 (q), 123.4, 123.0, 121.2, 120.0 (q), 116.6, 116.5 (q), 113.0, 112.6 (dd), 105.8 (dd), 19.7
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC#Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of compound 51 (2.01 g, 6.923 mmol) in ethanol (50 mL) was added 10% palladium on carbon (737 mg, wet) in one portion under argon protection. The flask was evacuated and re-filled with argon three times (to remove oxygen), and the mixture stirred at room temperature overnight under one atmosphere of hydrogen. The reaction system was then purged with nitrogen, and the catalyst was vacuum filtered and washed with ethanol (2×5 mL). The filtrate and washings were combined and concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0–25%) and hexanes (100–75%), to afford 1.75 g (96%) of the product 52 as a colorless viscous oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.47–1.64 (m, 4H), 2.50 (t, J=7.1 Hz, 2H), 3.08–3.14 (m, 2H), 3.57 (br s, 2H), 4.55 (br s, 1H), 6.62 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H). m/z (APCI)=265 [C15H24N2O2+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[N:16]1([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH2:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1ccc(N2CC=C(N3CCCC3)CC2)cc1

Procedure:
A solution of 24 g (0.1199 mol) of the compound of (B), 15 ml (12.78 g/0.1796 mol) of pyrrolidine, 240 mg of p-toluenesulfonic acid, and 100 ml of benzene is stirred at reflux with the azeotropic removal of water for 6 hours. After cooling, the resulting precipitate is collected and triturated with ethyl ether to afford 20 (66%) of title compound: m.p. 126°-129° C.; IR (KBr) 2200, 1635, and 1600 cm-1 ; NMR (CDCl3) δ7.48 (d, 2H), 6.7 (d, 2H), 4.3-4.1 (m, 1H) 3.95-3.45 (m, 4H), 3.2-2.85 (m, 4H) 2.65-2.25 (m, 2H), and 1.95-1.75 (m, 4H).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(Br)C.N#N.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1C#N.[NH4+].[Cl-]>O.C1COCC1>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: N#Cc1ccccc1F
Reactant: CN1CCC(Cl)CC1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCBr
Product: CN1CCC(c2ccccc2F)CC1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
800 ml of THF solution of 4-chloro-N-methylpiperidine (245 g, 1.8 mol) is drop-added slowly to 250 ml of tetrahydrofuran wherein Mg powder (55.7 g, 2.3 mol) and small amount of ethyl bromide are added under coverage of N2. After completion of drop-addition, a reaction is carried out at reflux for one hour. The reaction solution is drop-added 440 ml of THF solution of 2-fluorobenzonitrile (222 g, 1.8 mol). After completion of drop-addition, a reaction is carried out at reflux for 3 hours and at room temperature for 13 hours; thereafter the reaction solution is poured into 2.3 L of water containing 700 g of NH4Cl and then reflux for 2 hours. The reaction solution is cooled and then is extracted with diethyl ether, and the extracting solutions are combined, evaporated to dryness and fractioned. The fractions at 124° C. are collected to obtain 224 g of a product.
Reaction SMILES: Cl.[CH:2]1([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[NH2:11])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].CO.C(Cl)Cl>C(Cl)Cl>[CH:2]1([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]([S:20]([CH3:19])(=[O:22])=[O:21])[S:20]([CH3:19])(=[O:22])=[O:21])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cnccc1C1CC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cnccc1C1CC1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A suspension of 4-cyclopropylpyridin-3-amine hydrochloride (297 mg, 1.741 mmol) in anhydrous CH2Cl2 (8.5 mL) was cooled to 0° C. and treated with triethylamine (0.849 mL, 6.09 mmol) and methanesulfonyl chloride (0.298 mL, 3.83 mmol). The mixture was stirred at 0° C. for 1 hour, then at room temperature for 1 hour. TLC (SiO2, 5% methanol/CH2Cl2; used sample of free base 10036010-0967 as starting material reference) showed the reaction was complete. The mixture was diluted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3 (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give a tan solid. The solid was purified by SiO2 flash chromatography (3.8 cm×10 cm) eluting with 3% methanol/CH2Cl2 to afford the product as a white solid (403 mg).
Reaction SMILES: C(O[C:6]([N:8]1CC[CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.[C:31]1(NCCN)[CH:36]=[CH:35]C=[CH:33][CH:32]=1>>[C:6]1([NH:8][CH2:9][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1
Reactant: NCCNc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCNc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using N-phenylethylenediamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 378 (M+H) 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.00 (1H, d, J=5.66 Hz) 7.62 (1H, d, J=5.42 Hz) 7.45 (1H, d, J=5.37 Hz) 7.25 (1H, d, J=3.56 Hz) 7.07 (2H, dd, J=8.66, 7.30 Hz) 6.86 (1H, d, J=5.66 Hz) 6.51-6.67 (4H, m) 3.55 (2H, t, J=6.47 Hz) 3.25-3.30 (2H, m)
Reaction SMILES: [H-].[Na+].C([Si]([S:13][Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C)(C)C.Br[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])[CH:31]=2)[CH:26]=1>O1CCCC1.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([SH:13])[CH:34]=[CH:33]2
Reactant: CC(C)[Si](S[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Reactant: Fc1ccc(-c2ccc3cc(Br)ccc3c2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc3cc(S)ccc3c2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.25 mmol) was added to a solution of triisopropylsilyl sulfide (1.2 mL, 5.59 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction was stirred at 0° C. for 5 minutes then at room temperature for 20 minutes. 2-Bromo-6-(2,4-difluorophenyl)naphthalene (Step 1, 1.63 g, 5.11 mmol) in toluene (30 mL) and tetrakis(triphenylphosphine)palladium(0) (310 mg) were added and the mixture degassed. The reaction was heated to reflux for 3 hours. The cooled reaction mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was suspended in isohexane and silica added. The mixture was filtered, washing the silica with isohexane. The filtrate was evaporated in vacuo and the residue dissolved in tetrahydrofuran (6 mL) and cooled to 0° C. A solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 3 mL) was added and the reaction stirred at 0° C. for 30 minutes. Water was added then 2M hydrochloric acid. The reaction mixture was extracted with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by filtration through a plug of silica, eluting with 10% dichloromethane/isohexane, to give 6-(2,4-difluorophenyl)-2-naphthyl hydrosulfide (0.78 g, contains some impurities). 1H NMR (500 MHz, CDCl3) δ 7.89 (1H, s), 7.77-7.74 (3H, m), 7.62-7.59 (1H, m), 7.52-7.46 (1H, m), 7.37 (1H, dd, J=1.8, 8.5 Hz), 7.01-6.93 (2H, m), 3.62 (1H, s).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)=[CH:26][N:25]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)(=O)=O>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]#[C:22][C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[N:13]([CH2:12][CH2:11][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:14]=[CH:15]4)=[N:25][CH:26]=2)=[CH:31][CH:32]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCN4CCCC4)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.1 mL (13.3 mmol) pyrrolidine are added to a solution of 600 mg (1.33 mmol) 2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl methanesulphonate in 12 mL DMF and the reaction mixture is stirred for 24 h at RT. The mixture is evaporated down i. vac., the residue is taken up in a little DCM and the product is purified by chromatography (silica gel, cyc/EtOAc 2:1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][N:19]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>CCOC(C)=O>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:3][C:2]=2[F:1])=[O:23])=[CH:20][N:19]=1
Reactant: Nc1ccc(-c2ccc(F)cc2F)cc1F
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2ccc(F)cc2F)cc1F)c1ccc(Cl)nc1

Procedure:
6-Chloro-N-(3,2′,4′-trifluoro-biphenyl-4-yl)-nicotinamide was prepared from 3,2′,4′-trifluoro-biphenyl-4-yl amine and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after a silica gel column chromatography with 0-30% EtOAc in hexanes. H1 NMR (300 MHz, chloroform-d) d ppm 6.91 (m, 2H), 7.15 (apparent t, J=8.1 Hz, 1H), 7.24-7.1 (m, 3H), 7.95 (dd, J=10.5 8.1 Hz, 2H), 8.69 (d, J=2.1 Hz, 2H).
Reaction SMILES: COC1C=C[C:6]([CH2:9][CH2:10][O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=CC=1.C[O:17]C1C=CC(CCO)=CC=1>C(C1OC1)Cl.[OH-].[Na+].[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[CH2:12]([O:11][CH2:10][CH:9]1[O:17][CH2:6]1)[CH:13]1[O:15][CH2:14]1
Reactant: COc1ccc(CCO)cc1
Reactant: COc1ccc(CCOCC2CO2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCC1CO1
Product: C(OCC1CO1)C1CO1
Yield: 67 %

Procedure:
1-[2-(4-methoxyphenyl)ethoxy]-2,3-epoxypropane (24.1). By condensation of 4.8 g (31.5 mmol) of 4-methoxyphenethyl alcohol in a mixture of 25 ml of epichlorohydrin and 18 ml of 50% caustic soda and 430 mg of Bu4NHSO4 according to process 23.1, 4.42 g (yield: 67%) of glycidyl ether of formula 24.1 are prepared: