Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][NH:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)([O-:3])=[O:2].[CH3:22][N:23]=[C:24]=[O:25]>CCOCC>[CH3:22][NH:23][C:24]([N:10]1[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[NH:13][C:12](=[O:14])[CH2:11]1)=[O:25]
Reactant: CN=C=O
Reactant: O=C1CNC(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Solvent: CCOCC
Product: CNC(=O)N1CC(=O)Nc2ccc([N+](=O)[O-])cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
5.6 g. (0.02 moles) of 7-nitro-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are suspended in 25 ml. of dry ether, and 4.8 ml. (0.08 moles) of methyl isocyanate are added to the suspension. The reaction mixture is stirred at room temperature for 16 hours, thereafter the solid crystalline substance is filtered off and washed with ether. 6.03 g. (97.6%) of 4-methylcarbamoyl-5-phenyl-7-nitro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained, m.p.: 176°- 180° C. After recrystallization from ethanol, the product melts at 179°- 180° C. Rf2 = 0.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.Br[CH:11]([CH2:14][C:15]([CH3:20])([N+:17]([O-:19])=[O:18])[CH3:16])[CH:12]=O>ClCCl>[CH3:16][C:15]([N+:17]([O-:19])=[O:18])([CH3:20])[CH2:14][C:11]1[N:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]2=[N:1][CH:12]=1
Reactant: CC(C)(CC(Br)C=O)[N+](=O)[O-]
Reactant: COc1ccc(N)nc1
Solvent: ClCCl
Product: COc1ccc2ncc(CC(C)(C)[N+](=O)[O-])n2c1
Yield: 42.1 %

Procedure:
2-Amino-5-methoxypyridine (J. Med. Chem., 24:39, 1981; 2.02 g, 16.3 mmol) and 2-bromo-4-methyl-4-nitropentanal (16.3 mmol) are reacted as described in Amine 7 and the product is isolated in two crops from the concentrated mixture by heating twice with dichloromethane (30 ml and 10 ml) and filtration without further chromatographic purification to give 1.71 g of 3-(2-methyl-2-nitropropyl)-6-methoxyimidazo[1,2-a]pyridine (42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[CH:6]=[C:5]2O.[H-].[Na+].FC(F)(F)S(N(C1C=CC=CC=1)S(C(F)(F)F)(=O)=O)(=O)=O.N1C2C(=CC=CC=2)C=CC1=O.[CH2:53]([O:55][C:56]([N:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]1)=[O:57])[CH3:54]>C(#N)C>[CH2:53]([O:55][C:56]([N:58]1[CH2:59][CH2:60][CH:61]([NH:64][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[CH:6]=2)[CH2:62][CH2:63]1)=[O:57])[CH3:54]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=c1cc(O)c2cc(Cl)ccc2n1CC(F)(F)F
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=c1ccc2ccccc2[nH]1
Agent: [H-]
Solvent: CC#N
Product: CCOC(=O)N1CCC(Nc2cc(=O)n(CC(F)(F)F)c3ccc(Cl)cc23)CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 58.5 %

Procedure:
6-Chloro-4-hydroxy-1-(2,2,2-trifluoroethyl)-1H-quinolin-2-one (0.996 g, 3.6 mmol) was suspended in dry acetonitrile (50 mL) under argon and treated with sodium hydride (0.16 g, 60% wt in mineral oil, 4 mmol). After stirring for 10 minutes, 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (1.36 g, 3.8 mmol) was added and the mixture heated to 50° C. for 6 hours. Analysis by LC/MS indicated the starting quinolone had been completely consumed and 4-aminopiperidine-1-carboxylic acid ethyl ester (770 μL, 4.5 mmol) was added. The reaction was heated to reflux for 18 hours at which time LC/MS analysis indicated complete consumption of the intermediate triflate. The solution was diluted with ethyl acetate and washed with 1 N NaOH. The organic layer was dried with sodium sulfate and concentrated under reduced pressure to give the crude product. This material was purified by silica chromatography using DCM and methanol eluent gave the title compound (0.91 g). 1H NMR (300 MHz, CDCl3) δ ppm 1.31 (5H, t, J=7.03 Hz), 2.02 (2H, m), 2.85 (2H, m), 3.50 (1H, m), 4.05 (2H, q, J=7.02 Hz), 4.80-5.11 (4H, m), 5.78 (1H, s), 7.28 (2H, m), 7.52 (2H, m).
Reaction SMILES: O[C:2]1([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH:7]2[CH2:9][CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.S(Cl)(Cl)=O.[OH-].[K+]>C(O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:2]2[CH:3]3[CH2:9][CH:7]([CH:8]=2)[CH2:6][NH:5][CH2:4]3)[CH:16]=1
Reactant: CCOC(=O)N1CC2CC(C1)C(O)(c1cccnc1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: C1=C(c2cccnc2)C2CNCC1C2
Temperature: 25 °C
Yield: 47 %

Procedure:
To ethyl 6-hydroxy-6-(3-pyridinyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (1.10 g, 4.0 mmol) was added thionyl chloride (5 ml) and the mixture was heated to reflux for 1 h under nitrogen. Thionyl chloride was removed by azeotropic rotary evaporation with toluene to give a dark brown oil, which was suspended in a 20% solution of potassium hydroxide in ethanol (10 ml) and refluxed for 18 h. The reaction mixture was cooled to room temperature and concentrated by rotary evaporation. Then saturated sodium chloride solution (10 ml) was added. The mixture was filtered. The collected solids were washed with chloroform (25 ml), and the filtrate was extracted with chloroform (3×25 ml). The combined chloroform extracts were dried over sodium sulfate, filtered, concentrated by rotary evaporation, and distilled on a Kugelrohr apparatus to yield a light brown oil (350 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[C:35]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:34][N:33]=[N:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:40][CH2:41][CH:36]([C:35]6[NH:34][N:33]=[N:32][N:31]=6)[CH2:37][CH2:38]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C1CC(c2nnn[nH]2)CCN1
Product: O=C1N=C(N2CCC(c3nnn[nH]3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-(1H-tetrazol-5-yl)-piperidine following General Procedure B.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:17].[BH4-].[Na+].O>C(O)(C)C>[OH:2][CH2:3][CH2:4][CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:17]
Reactant: COC(=O)CC1CCCCCCCCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OCCC1CCCCCCCCCCC1O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
The crude ketoester (IX) from step 4 (approximately 180 gm; 0.7 mol) was refluxed for 8 hours with agitation under nitrogen with 74 gm (1.96 mol) of sodium borohydride in 1250 ml of isopropanol. After addition of 150 ml of water, the mixture was agitated for 30 minutes at 60° C., and any sodium borohydride remaining was destroyed by the addition of 100 ml of acetone with good cooling. After agitation for another 30 minutes, the isopropanol was distilled off with the simultaneous addition of 200 ml water. After cooling to approximately 30° to 35° C., the residue was neutralized with half-concentrated sulfuric acid and mixed with 700 ml of toluene. The aqueous phase was separated. The toluene phase contained approximately 135 gm of 1,4-diol (IV) (85% yield) and was used further without evaporation.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[C:23]1[N:27]2[CH:28]=[C:29](F)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1>CN(C=O)C.O>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[C:23]1[N:27]2[CH:28]=[C:29]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.2 %

Procedure:
To a solution of Intermediate 1 (6.59 g, 40.4 mmol) in dry DMF (80 mL) under N2 was added sodium hydride (60% dispersion in oil, 3.20 g, 80.0 mmol) and the resulting opaque brown solution was stirred at RT for 45 min (CARE: gas evolution). A solution of Intermediate 3c (9.93 g, 40.0 mmol) in dry DMF (20 mL) was added and the solution stirred at RT for 24 h. The reaction was carefully quenched with saturated NH4Cl (CARE: gas evolution) solution and H2O. The brown mixture was stirred for 30 min. The mixture was concentrated in vacuo and dissolved in MeOH (125 mL), charcoal was added to the solution and the mixture was stirred at RT for 1 h, and then filtered through Celite. The solution was evaporated under reduced pressure to afford a residue, which was suspended in H2O (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (75 mL), dried over Na2SO4, filtered and concentrated in vacuo to leave a brown foam (14.6 g, 93%). The foam was triturated with pentane (2×75 mL) using sonication and stirring, the solution was decanted and the solid was left to dry under vacuum and at RT affording a solid (14.2 g, 90%). LCMS (Method 3): Rt 2.32 min, m/z 392 [Mf1+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=C[CH:14]=1)[CH:8]=[CH:7]2.BrC1C=CC=C2C=1[N:28]=C(Cl)C=C2.N1C=CC=C(N)C=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:14]=[N:28][CH:16]=[CH:17][CH:18]=1)[CH:8]=[CH:7]2
Reactant: Clc1ccc2cccc(Br)c2n1
Reactant: Brc1cccc2ccc(Nc3ccccc3)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Nc1cccnc1
Agent: [Li+]
Product: Brc1cccc2ccc(Nc3cccnc3)nc12
Yield: 57 %

Procedure:
This compound (1.03 g, 57% yield) as a tan crystalline solid was prepared similarly to that described in the preparation of 165c, using 8-bromo-2-chloroquinoline (Biofine International, Vancouver, BC; 1.46 g, 6.02 mmol), pyridin-3-amine (Aldrich; 0.68 g, 7.22 mmol), and LiHMDS (1.0 M solution in THF; 15.05 mL, 15.05 mmol) as starting materials. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.93 (1H, s), 9.20 (1H, d, J=2.3 Hz), 8.84 (1H, d, J=8.4 Hz), 8.24-8.13 (2H, m), 7.99 (1H, d, J=7.6 Hz), 7.82 (1H, d, J=7.6 Hz), 7.39 (1H, dd, J=8.4, 4.7 Hz), 7.26 (1H, t, J=7.7 Hz), 7.18 (1H, d, J=8.8 Hz). m/z (ESI, +ve) 300/302 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([NH2:13])[N:3]=1.[CH3:14][C@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([CH3:24])=[CH:20][CH:21]=2)[C@@H:16]1[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:8][C:7]1[C:2]([NH:25][C@H:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([CH3:24])[CH:18]=3)[CH2:23][C@@H:15]2[CH3:14])=[N:3][C:4]([NH2:13])=[N:5][C:6]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1nc(Cl)c(Cl)c(C(F)(F)F)n1
Reactant: Cc1ccc2c(c1)[C@H](N)[C@@H](C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc2c(c1)[C@H](Nc1nc(N)nc(C(F)(F)F)c1Cl)[C@@H](C)C2
Temperature: 125 °C
Yield: 58 %

Procedure:
A mixture of 0.10 g (0.43 mmol) of 4,5-dichloro-6-(trifluoromethyl)pyrimidin-2-amine, 0.08 g (0.51 mmol) of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine and 0.14 g (1.3 mmol) of potassium carbonate in 1 ml of dimethylacetamide as solvent is heated at 125° C. for 30 minutes in a microwave appliance (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture is absorbed on silica gel and, following column chromatographic separation, 0.089 g of 5-chloro-N4-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-6-(trifluoromethyl)pyrimidin-2,4-diamine is obtained (solid, 55% yield, 95% purity).
Reaction SMILES: COCCOCCOC.N.[C:11](#[N:20])[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[H][H]>O>[C:12]1([CH2:11][NH2:20])[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: N
Solvent: COCCOCCOC
Solvent: O
Product: NCc1ccc(CN)cc1
Temperature: 125 °C

Procedure:
A stirred autoclave is charged with 900 ml. of diethylene glycol dimethyl ether (Diglyme), 100 ml. ammonia, 100 g. terephthalonitrile (TPN) and the desired amount of catalyst and 100 ml of water. The autoclave is heated to 125° C. Hydrogen is introduced rapidly until the selected pressure is reached. The absorption of hydrogen starts immediately and additional hydrogen is added to keep the pressure at the selected level. The course of the reaction is monitored by measuring the volume of hydrogen consumed and by periodic withdrawal of a small sample of the reaction mixture for analysis. When the analysis indicates that all of the terephthalonitrile is reacted, the agitation is stopped and the reactor is cooled rapidly and vented. The reaction mixture is filtered to recover the catalyst and then is flash evaporated to remove solvent. The residual oil is distilled at about 100° C. and 0.5 mm Hg. to give practically pure p-xylylene diamine. A small amount of high boiling residue remains in the distillation pot.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](Cl)=[O:24])=[CH:22][C:17]=2[O:16][CH2:15]1>CN(C1C=CN=CC=1)C>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:24])/[CH:13]=[C:7]3\[S:8][C:9]([CH3:12])=[C:10]([CH3:11])[N:6]\3[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by benzo[d][1,3]dioxole-5-carbonyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.93 (t, 3 H) 1.34-1.44 (m, 2 H) 1.58-1.68 (m, 2 H) 2.16 (s, 3 H) 2.20 (s, 3 H) 4.02-4.09 (m, 2 H) 6.08 (s, 2 H) 6.48 (s, 1 H) 6.93-6.99 (m, 1 H) 7.47-7.48 (m, 1 H) 7.49-7.54 (m, 1 H); MS (ESI) m/z 332 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[C:12]([CH:13]=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:15])[CH:9]=2)[N:4]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][N:2]([CH3:16])[C:3]1[C:12]([CH2:13][OH:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:15])[CH:9]=2)[N:4]=1
Reactant: Cc1ccc2nc(N(C)C)c(C=O)cc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc2nc(N(C)C)c(CO)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred solution of 2-(dimethylamino)-6-methylquinoline-3-carbaldehyde RBO 35148 (988 mg, 4.61 mmol) in a mixture EtOH:THF=50 mL:20 mL in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (174 mg, 4.61 mmol) and the mixture was stirred overnight at RT, cooled in an ice bath and treated by a 6 N aq. HCl solution (2 mL). After stirring for 1 h at 4° C., the mixture was brought to pH=9 with a 2N aq. NaOH solution (6 mL). Volatiles were removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (50 mL). The organic layer was washed with water (3×20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (2-(dimethylamino)-6-methylquinolin-3-yl)methanol RBO 40152 as yellow oil (900 mg, 90% yield).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]5[C:31](=[O:43])[N:32]([C:36]6[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=6)[N:33]=[CH:34][CH:35]=5)=[O:29])=[CH:23][C:22]=4[F:44])[CH:12]=3)=[CH:7][CH2:6]2)[O:4]CC1>C(O)(C(F)(F)F)=O>[F:44][C:22]1[CH:23]=[C:24]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[N:33]=[CH:34][CH:35]=2)=[O:29])[CH:25]=[CH:26][C:21]=1[O:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:12]=[C:11]([C:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]=3)[S:19][C:18]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC=C(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 28.7 %

Procedure:
A round-bottomed flask was charged with N-(4-(2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (153 mg, 0.249-mmol) and CF3COOH (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the solvent was removed and the residue was purified by silica gel chromatography (dichloromethane/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (40.8 mg, 28.7%). LRMS (APCI pos): >99% purity, 254 nm, m/e 571 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.84 (s, 1H), 8.45 (d, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 7.96 (d, 1H), 7.58-7.62 (m, 2H), 7.40 (m, 1H), 7.20-7.28 (m, 4H), 6.51 (d, 1H), 6.42 (m, 1H), 3.14 (m, 2H), 3.02 (m, 2H), 2.71 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Cl.[CH3:20][NH2:21]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CN
Agent: Cl
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Yield: 70.2 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (500 mg, 1.766 mmol) and methanamine hydrochloride (179 mg, 2.65 mmol) were combined and purified as per Preparation Ha to give 2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (344 mg, 1.239 mmol, 70.1% yield). LC-MS (M+H)+=278.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.03-7.12 (2 H, m), 6.91-7.03 (2 H, m), 4.53-4.79 (1 H, m), 4.19-4.29 (1 H, m), 3.09 (3 H, d, J=4.88 Hz), 2.56-2.80 (3 H, m), 2.00-2.15 (1 H, m).
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][O:8][NH3+:9].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=1.O>CCCCCC.O1CCCC1>[CH3:7][O:8][NH:9][C:14]1[N:13]=[C:12]([O:11][CH3:10])[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]=1
Reactant: CO[NH3+]
Reactant: COc1cc(C(F)(F)F)nc(S(C)(=O)=O)n1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CONc1nc(OC)cc(C(F)(F)F)n1
Reaction time: 0.17 h
Yield: 43.1 %

Procedure:
66.6 g of a 1.6 molar solution of n-butyllithium (0.156 mol) in n-hexane were added dropwise to a solution of 6.5 g of O-methylhydroxylammonium chloride (78 mmol) in 200 ml of tetrahydrofuran at -10° C. Stirring was carried out for 10 minutes at -10° C., and 20 g of 4-methoxy-2-methylsulfonyl-6-trifluoromethylpyrimidine (78 mmol) were added to the cloudy solution. Stirring was carried out for 1 hour at 25° C., the reaction batch was introduced into 200 ml of water, and the organic phase was separated off, washed with water and dried. Removal of the solvent gave an oily, slightly impure product, which could be crystallized in pentane at -78° C. 7.5 g of the product (43% of theory) were obtained as colorless crystals of melting point. 44°-46° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.OC1C2N=NNC=2C=CC=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C.[C:49]([C:51]1[N:56]=[CH:55][C:54]([C:57]2[C:69]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]([C:70]4[CH:78]=[CH:77][C:73]([C:74]([OH:76])=O)=[C:72]([NH:79][CH2:80][CH2:81][C:82]([OH:85])([CH3:84])[CH3:83])[CH:71]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)#[N:50]>CN(C)C=O.O>[C:49]([C:51]1[N:56]=[CH:55][C:54]([C:57]2[C:69]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]([C:70]4[CH:78]=[CH:77][C:73]([C:74]([NH2:8])=[O:76])=[C:72]([NH:79][CH2:80][CH2:81][C:82]([OH:85])([CH3:83])[CH3:84])[CH:71]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)#[N:50]
Reactant: CC(C)(O)CCNc1cc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)ccc1C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Oc1cccc2[nH]nnc12
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)CCNc1cc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.5 %

Procedure:
108 mg of (1H-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (BOP), 33 mg of hydroxybenzotriazole (HOBT), 17 mg of ammonium chloride and 0.1 ml of diisopropylethylamine are successively added to a solution of 80 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxy-3-methylbutyl)amino]benzoic acid in 10 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 12 hours and then diluted with distilled water and extracted with ethyl acetate. The organic phase is subsequently washed with distilled water and a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (96/4 by volume), so as to give 18 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxy-3-methylbutyl)amino]benzamide in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].Cl>C1(C)C=CC=CC=1>[C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(=O)Nc1ccc(Br)cc1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of 4-bromoaniline (9.0 g, 52.3 mmol) in PhMe (100 mL) and pyridine (8.5 mL, 110 mmol, 2.0 eq.) was cooled in an ice bath and slowly treated with propionyl chloride (5.5 mL, 63 mmol, 1.2 eq.). After 2 h, the reaction mixture was added to 0.1 M HCl and extracted into EtOAc. Concentration followed by recrystallization of the residue from EtOH/water gave N-propionyl-4-bromoaniline (10.64 g, 89%). [M−H]−=278.1 m/z.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([O:21][CH3:22])=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1.[H][H]>O1CCCC1.C(O)C.[Pd]>[NH2:8][CH2:9][CH:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([O:21][CH3:22])=[CH:14][CH:13]=1)[OH:11]
Reactant: COc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C(O)CN)cc1C(N)=O

Procedure:
A solution of 5-(N,N-dibenzylglycyl)-o-anisamide (3.88g) in tetrahydrofuran (25 ml) and ethanol (125ml) was added to a pre-reduced suspension of 10% Pd/C (1.0g) in ethanol (25 ml). Uptake of hydrogen ceased within 14 hours. The catalyst was filtered off and the solvent evaporated under reduced pressure to leave 5-(2-amino-1-hydroxyethyl)-o-anisamide as a colourless gum.