Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[F:21][C:22]([F:27])([F:26])[C:23](O)=[O:24]>C(Cl)Cl>[ClH:1].[F:21][C:22]([F:27])([F:26])[C:23]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:24]
Reactant: NCCCSc1ccncc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)C(F)(F)F
Yield: 60.1 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.70 ml (4.96 mmol) of anhydrous trifluoroacetic acid under ice-cooling with stirring and the mixture was stirred for at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to, obtain the powder which was washed with hexane and dried to obtain 750 mg of the desired compound (free base) (68.4%, pale yellow prisms).
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:31][NH:32][CH2:33][C:34]([NH2:36])=[O:35].[CH2:37]([C:39]1[CH:40]=[CH:41][C:42]([F:66])=[C:43]([C:45]2[CH:46]=[N:47][C:48]([N:51]3[C:59]4[C:54](=[CH:55][CH:56]=[C:57]([C:60]([OH:62])=O)[CH:58]=4)[C:53]([CH:63]([OH:65])[CH3:64])=[CH:52]3)=[N:49][CH:50]=2)[CH:44]=1)[CH3:38]>CN(C=O)C>[NH2:36][C:34](=[O:35])[CH2:33][N:32]([CH3:31])[C:60]([C:57]1[CH:58]=[C:59]2[C:54]([C:53]([CH:63]([OH:65])[CH3:64])=[CH:52][N:51]2[C:48]2[N:47]=[CH:46][C:45]([C:43]3[CH:44]=[C:39]([CH2:37][CH3:38])[CH:40]=[CH:41][C:42]=3[F:66])=[CH:50][N:49]=2)=[CH:55][CH:56]=1)=[O:62]
Reactant: CNCC(N)=O
Reactant: CCc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)O)cc43)nc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-methylmorpholine (0.107 mL, 0.986 mmol), TBTU (0.191 g, 0.592 mmol) and 2-(methylamino)acetamide hydrochloride (0.123 g, 0.986 mmol) were added to an ice-cooled suspension of 331e) (0.2 g, 0.493 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with ice-cold water. A precipitate was filtered off and dissolved in dichloromethane. The organic phase was washed with sodium hydrogen carbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate and evaporated. The remnant was purified by flash column chromatography [silica gel; dichloromethane with 4% methanol] followed by preparative HPLC. White solid. Yield: 65 mg (28% of theory)
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:21][O:20][CH2:19]3)[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([NH:28][C:29]1[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:36][C:37]([C:41]1[N:28]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([CH:18]5[CH2:21][O:20][CH2:19]5)[CH2:16][CH2:17]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:6]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]=1)([F:42])[CH3:38]
Reactant: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(-n3c(C(C)(F)F)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.1 %

Procedure:
To a mixture of N-[9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-ylpiperidin-1-ylmethyl)-9H-purin-2-yl]benzene-1,2-diamine (0.115 g, 0.24 mmol) and 2,2-difluoropropionic acid (0.028 g, 0.25 mmol) and DIPEA (0.091 mL, 0.53 mL) in DMF (7 mL) was added HATU (0.11 g, 0.29 mmol). The reaction mixture was stirred at room temperature for 24 h, then at 90° C. for 24 h. The reaction mixture was concentrated in vacuo and the residue was loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted with 2 M NH3 in MeOH. The solution was concentrated in vacuo, the residue was diluted in acetic acid (15 mL) and the reaction mixture was stirred at 90° C. for 7 h. The reaction mixture was concentrated in vacuo and the resultant residue was purified by flash chromatography (Si—PPC, MeOH:DCM, 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 459 as a white solid (0.032 g, 27%). LCMS (Method I): RT=3.30 min, [M+H]+ 553.3. 1H NMR (400 MHz, DMSO-d6): δ 7.84-7.81 (m, 1 H); 7.74-7.71 (m, 1 H); 7.43-7.35 (m, 2 H); 4.40-4.15 (m, 4 H); 3.84 (s, 2 H); 3.81 (d, J=4.3 Hz, 2 H); 3.78-3.71 (m, 7 H); 3.37 (t, J=6.9 Hz, 2 H); 3.30-3.18 (m, 2 H); 2.96 (t, J=6.9 Hz, 2 H); 2.34-2.21 (t, J=19.5 Hz, 3 H); 2.20-2.08 (m, 1 H); 1.64 (d, J=12.1 Hz, 1 H); 1.50 (d, J=13.0 Hz, 2 H); 1.06 (td, J=12.1, 4.3 Hz, 2 H)
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:19][C:20]1([CH3:26])[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:19][C:20]1([CH3:26])[CH2:24][N:23]([C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[C:22](=[O:25])[CH2:21]1
Reactant: CC1(C)CNC(=O)C1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC1(C)CC(=O)N(c2ncc(C#Cc3ccccc3)cn2)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.2 %

Procedure:
(100 mg, 0.39 mmol) 2-Methanesulfonyl-5-phenylethynyl-pyrimidine (Example 115, step 1) was dissolved in 1 ml dioxane. 4,4-Dimethylpyrrolidin-2-one (53 mg, 465 μmol, 1.2 equiv.) and cesium carbonate (190 mg, 580 μmol, 1.5 equiv.) were added at room temperature. The mixture was stirred for 4 hours at 100° C. The reaction mixture was cooled, evaporated and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (32 mg, 28% yield) was obtained as a light yellow solid, MS: m/e=292.1 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:16]1)(=[O:14])=[O:13])=[CH:6]2.C(N(C(C)C)CC)(C)C.[C:50](=O)([O:58]C1C=CC([N+]([O-])=O)=CC=1)[O:51][CH:52]([O:54][C:55](=[O:57])[CH3:56])[CH3:53]>C(O)C>[C:55]([O:54][CH:52]([O:51][C:50]([CH:28]1[NH:27][CH2:26][C:25]2[S:24][C:23]([C:21]([N:18]3[CH2:19][CH2:20][N:15]([S:12]([C:7]4[NH:8][C:9]5[C:5]([CH:6]=4)=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=5)(=[O:13])=[O:14])[CH2:16][CH:17]3[CH2:32][C:33]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[O:34])=[O:22])=[N:31][C:30]=2[CH2:29]1)=[O:58])[CH3:53])(=[O:57])[CH3:56]
Reactant: O=C(CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(s1)CNCC2)N1CCOCC1
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(=O)OC(C)OC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)N3CCOCC3)sc2CN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In ethanol (6 ml) was dissolved 4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (200 mg), followed by the addition of diisopropylethylamine (83 μl) and 1-acetoxyethyl p-nitrophenyl carbonate (128 mg). The resulting mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure. Methylene chloride and an aqueous solution of sodium bicarbonate were added and the mixture was separated into layers. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated. The residue was purified by chromatography on a silica gel column (1-2% methanol-methylene chloride). The product was dissolved in ethyl acetate, followed by crystallization from diethyl ether, whereby the title compound (100 mg) was obtained as colorless powder.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:22]([O:31][CH2:32][CH2:33][OH:34])[N:21]=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[Br:35][C:36]1[CH:37]=[N:38][C:39](Cl)=[N:40][CH:41]=1.Cl>CC(N(C)C)=O.O1CCCC1>[Br:35][C:36]1[CH:37]=[N:38][C:39]([O:3][CH2:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[C:23]([C:24]4[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[C:22]([O:31][CH2:32][CH2:33][O:34][C:39]4[N:40]=[CH:41][C:36]([Br:35])=[CH:37][N:38]=4)[N:21]=[CH:20][N:19]=3)(=[O:15])=[O:16])=[CH:10][CH:9]=2)([CH3:7])[CH3:6])=[N:40][CH:41]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)CO)cc3)ncnc2OCCO)cc1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)COc4ncc(Br)cn4)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 33.8 %

Procedure:
To a suspension of sodium hydride (65 mg) in dimethylacetamide (0.5 ml) and tetrahydrofuran (0.5 ml) is added dropwise a solution of 4-(2-hydroxy-1,1-dimethylethyl)-N-{6-[2-hydroxyethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (135 mg) in dimethylacetamide (2 ml) and THF (2 ml) solution over period of 5 minutes at room temperature, and thereto is added 5-bromo-2-chloropyrimidine (399 mg). The mixture is stirred at room temperature for 6 days. The reaction mixture is acidified with cold diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The oily residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=100:1), and evaporated to remove the solvent. The resulting crude crystals are recrystallized from methylene chloride/isopropyl ether to give 4-[2-(5-bromopyrimidin-2-yloxy)-1,1-dimethylethyl]-N-{6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (77 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13](=O)[CH:12]([O:17][CH3:18])[CH2:11]2)=[CH:4][CH:3]=1.C([NH2:28])C1C=CC=CC=1.S1C=CC=C1>C1COCC1.[Pd]>[F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH2:28])[CH:12]([O:17][CH3:18])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC1CN(CCCOc2ccc(F)cc2)CCC1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: c1ccsc1
Product: COC1CN(CCCOc2ccc(F)cc2)CCC1N

Procedure:
A mixture of 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinone (140 mg, intermediate 1), benzylamine (61 mg), Pd 10% on charcoal (100 mg) and a 0.02% solution of thiophene in THF was reacted under hydrogen gas for 3 hours at 50° C. The catalyst was filtered off and fresh palladium 10% on charcoal (100 mg) was added. Debenzylation of the formed intermediate took place under hydrogen atmosphere for 18 hours at 50° C. The reaction mixture was filtered and evaporated under a gentle stream of nitrogen to yield 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (compound I-1) having a cis/trans ratio of about 93/7.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([O-:31])=[O:30])[C@H:26]([CH3:32])[C:25]([C:33]([F:36])([F:35])[F:34])=[N:24]4)=[CH:19][CH:18]=3)[C@H:12]([CH3:37])[CH2:11]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O[C:39]1C=CC(N2[C@@H](CC(OC)=O)[C@H](C)C(C(F)(F)F)=N2)=CC=1.ClC1C(N2CC[C@H](O)[C@H](C)C2)=CC(OC)=NC=1.C(P(CCCC)CCCC)CCC.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([O:31][CH3:39])=[O:30])[C@H:26]([CH3:32])[C:25]([C:33]([F:36])([F:34])[F:35])=[N:24]4)=[CH:21][CH:22]=3)[C@H:12]([CH3:37])[CH2:11]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1cc(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)[O-])cc3)[C@H](C)C2)c(Cl)cn1
Reactant: COC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: COc1cc(N2CC[C@H](O)[C@H](C)C2)c(Cl)cn1
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(O[C@@H]2CCN(c3cc(OC)ncc3Cl)C[C@H]2C)cc1
Temperature: 50 °C
Yield: 64 %

Procedure:
2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a solution of methyl 2-((4S,5S)-1-(4-hydroxyphenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (1J, 4.6 g, 15 mmol) and (3R,4S)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol (3.4 g, 13 mmol) in toluene (166 mL) was added tributylphosphine (5.5 mL, 21 mmol). While stirring, (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (5.4 g, 21 mmol) was added portionwise to the reaction mixture, and the resulting mixture was heated at 50° C. for 120 min. The mixture was cooled to rt and 150 mL of hexanes was added to the mixture and a white precipitate formed. The mixture was filtered, and the filtrate was concentrated and was purified via silica gel chromatography to give methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (4.7 g, 8.5 mmol, 64% yield). LC-MS Anal. Calc'd for C26H30ClF3N4O4 554.19. found [M+H] 555.2. 1H NMR (400 MHz, CDCl3) δ ppm 8.00 (s, 1H), 7.15-7.04 (m, 2H), 7.01-6.89 (m, 2H), 6.30 (s, 1H), 4.49-4.36 (m, 1H), 3.91 (s, 4H), 3.73 (s, 3H), 3.62-3.49 (m, 2H), 3.28-3.15 (m, 1H), 2.95-2.85 (m, 1H), 2.82 (dd, J=16.2, 3.2 Hz, 1H), 2.67 (dd, J=12.3, 9.0 Hz, 1H), 2.43 (dd, J=16.1, 10.3 Hz, 1H), 2.26-2.12 (m, 2H), 1.91-1.78 (m, 1H), 1.36 (d, J=7.0 Hz, 3H), 1.16 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([N+:22]([O-:24])=[O:23])[C:17]([CH3:21])=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C(O)(C(F)(F)F)=O>C(O)(C)C>[CH3:21][C:17]1[C:16]([N+:22]([O-:24])=[O:23])=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[N:12][CH:13]=[CH:14]2
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Reactant: N#Cc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1[N+](=O)[O-]
Temperature: 22 °C
Yield: 89.6 %

Procedure:
A mixture of 4-aminobenzonitrile (4.0 g, 34 mmol), isopropanol (50 mL) and 1-chloro-6-methyl-5-nitroisoquinoline (5.0 g, 22 mmol) was stirred at RT (22° C.) and treated with TFA (5.0 mL, 67 mmol). The reaction mixture was stirred at 80° C. for 17 h, and allowed to cool to RT. The thick slurry was diluted with isopropanol (100 mL) and the solid precipitate was collected by suction filtration. The solid was washed with saturated NaHCO3 (2×100 mL), water (50 mL), Et2O (50 mL), and hexane (100 mL) and dried in a vacuum oven at 70° C. overnight to provide 4-(6-methyl-5-nitroisoquinolin-1-ylamino)benzonitrile (6.0 g, 88% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 305 [M+H]+.
Reaction SMILES: [OH-].[Na+].Cl.[Br:4][C:5]1[CH:6]=[C:7]2[C:18]3([CH2:23][CH2:22][S:21][C:20]([NH:24]C(=O)C4C=CC([N+]([O-])=O)=CC=4)=[N:19]3)[C:17]3[CH:16]=[C:15]([Cl:36])[N:14]=[CH:13][C:12]=3[O:11][C:8]2=[CH:9][CH:10]=1>CO.O>[Br:4][C:5]1[CH:6]=[C:7]2[C:18]3([CH2:23][CH2:22][S:21][C:20]([NH2:24])=[N:19]3)[C:17]3[CH:16]=[C:15]([Cl:36])[N:14]=[CH:13][C:12]=3[O:11][C:8]2=[CH:9][CH:10]=1
Reactant: O=C(NC1=NC2(CCS1)c1cc(Br)ccc1Oc1cnc(Cl)cc12)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC1=NC2(CCS1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
A 2 N NaOH solution (24.47 ml, 48.9 mmol) was added to a solution of N-(7-bromo-3-chloro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazin]-2′-yl)-4-nitrobenzamide hydrochloride (9.5 g, 16.32 mmol) in MeOH (250 ml). The reaction mixture was heated to 65° C. for 3 hours. The reaction mixture was diluted with water (300 mL), stirred for 10 min, and then filtered. The solid was washed with water and dried under reduced pressure to afford 7-bromo-3-chloro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazin]-2′-amine (3.9 g, 9.83 mmol, 60.3% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)[Cl:15].C([O-])(O)=O.[Na+]>CCO>[Cl:15][CH2:14][CH:16]([OH:18])[CH2:17][N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)CN1CCN(Cc2ccccc2)CC1
Yield: 75.3 %

Procedure:
1-Benzylpiperazine (8.66 mL, 50 mmol) in EtOH (100 mL) was added dropwise to epichlorohydrin (3.92 mL, 50 mmol) in EtOH (25 mL) with NaHCO3 (4.2 g, 50 mmol) over 30 min at 0° C. under nitrogen. After 16 h the EtOH was removed in vacuo and the crude product eluted through silica gel (5% methanol: methylene chloride) to give pure product (10.12 g, 75.3%) as an amber oil. DCI/MS (M+1) 269. 400 MHz 1H NMR (CDCl3) δ: 7.3 (m, 5H), 4.95 (m, 1H), 4.5 & 4.6 (m, 2H), 3.95 (m, 1H), 3.6 (m, 2H), 3.5 (s, 2H), 2.7 (m, 4H), 2.4 (m, 4H).
Reaction SMILES: [O:1]1[CH2:25][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[NH3:26]>CCO>[NH2:26][CH2:25][CH:2]([OH:1])[CH2:3][N:4]1[CH2:5][CH2:6][N:7]([CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:8][CH2:9]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CC3CO3)CC2)cc1
Reactant: N
Solvent: CCO
Product: NCC(O)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A solution of 1-[1-(2,3-epoxy)propyl]-4-[bis(4-fluorophenyl)methyl]piperazine (8.9 g, 25.8 mmol) and liquid ammonia (20 mL) in EtOH (40 mL) was heated in a teflon reaction vessel in a bomb at 110° C. for 28 h. The solution was then evaporated to dryness to give about 10 g of a glass which was purified using flash chromatography on silica gel and increasing proportions of methanol in methylene chloride to give the product as an oil which solidified upon vacuum drying, 5.7 g (61%), mp 45°-47° C. IR(neat) 3350 cm-1 ; 300 MHz 1H NMR (CDCl3) δ: 7.4-6.9 (m, 8H), 4.21 (s, 1H), 3.68 (br m, 1H) 2.8-2.2 (m, 12H); MS 362 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:13]1([NH:12][C:9]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=2)=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
4-Nitropyrazole-3-carboxylic acid (2.5 g; 15.9 mmol) was added to a stirred solution of aniline (1.6 ml; 17.5 mmol), EDC (3.7 g; 19.1 mmol), and HOBt (2.6 g; 19.1 mmol) in N,N-dimethylformamide (DMF) (25 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate/saturated NaHCO3 solution. The resultant solid was collected by filtration, washed with water and diethyl ether then dried under vacuum to give 2.85 g of the title compound (sodium salt) as a yellow/brown solid. (LC/MS: Rt 2.78, [M+H]+ 232.95).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH2:29][N:30]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:59])=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]6)[CH:40]=5)[CH:38]=4)[CH3:31])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][NH:20][C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]([CH2:32][C:33]4[CH:38]=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]6)[CH:40]=5)[C:36]([F:59])=[CH:35][CH:34]=4)[CH3:31])[CH:24]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 20 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-phenyl}methyl)(methyl)amino]-methyl}-2′-fluoro-3-biphenylyl)methyl]-1-piperazinecarboxylate (0.386 g, 0.463 mmol) in DCM (3.6 mL) was added TFA (1.8 mL) and this mixture was stirred at room temperature for 100 min before being quenched with NaHCO3 (sat. aq.). This mixture was extracted with DCM, concentrated, purified using a Gilson HPLC (with TFA). Product was basified with an amine cartridge to afford 0.068 g (20%) of the title compound. LC-MS m/z 733 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J=7.65 Hz, 3 H) 1.49 (t, J=7.15 Hz, 3 H) 1.79-1.92 (m, 2 H) 2.05-2.14 (m, 2 H) 2.74 (s, 3 H) 3.18 (q, J=7.61 Hz, 2 H) 3.43-3.58 (m, 8 H) 3.63-3.72 (m, 2 H) 3.99-4.07 (m, 2 H) 4.30-4.62 (m, 9 H) 4.72 (s, 2 H) 7.34 (dd, J=10.42, 8.66 Hz, 1 H) 7.54-7.65 (m, 4 H) 7.67-7.78 (m, 4 H) 8.02 (d, J=8.03 Hz, 1 H) 8.12 (s, 1 H) 8.29 (s, 1 H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:7]=1[C:16]#[N:17])=[O:4].C(=O)(O)[O-:19].[Na+]>S(=O)(=O)(O)O>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:7]=1[C:16](=[O:19])[NH2:17])=[O:4]
Reactant: O=C([O-])O
Reactant: CCN(CC)c1nsc(NC(=O)NC)c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCN(CC)c1nsc(NC(=O)NC)c1C(N)=O
Temperature: 0 °C

Procedure:
A stirred mixture of 8.5 g of 1-methyl-3-(4-cyano-3-(diethylamino)-5-isothiazolyl)urea in 17 ml of concentrated sulfuric acid was heated at 100° during 11/4 hours. The reaction mixture was poured into 250 ml of stirred ice-water. The mixture became unstirrable and was then carefully poured into 1 liter of saturated sodium bicarbonate solution. The mixture was stirred during one and a quarter hours, filtered cold, and washed with cold water. The collected solid was recrystallized twice from ethanol to give 5.3 g of 1-methyl-3-(4-carbamoyl-3-(diethylamino)-5-isothiazolyl)urea; m.p. 195°-197°. The nmr spectrum was consistent with the assigned structure.