Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[C:6](=[S:18])[NH:5][C:4](=[O:19])[CH:3]=1.[N:20]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:20][C:3]1[C:4](=[O:19])[NH:5][C:6](=[S:18])[N:7]([CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[C:2]=1[NH2:1]
Reactant: Nc1cc(=O)[nH]c(=S)n1Cc1nc2ccccc2[nH]1
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(N)n(Cc2nc3ccccc3[nH]2)c(=S)[nH]c1=O
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a suspension of 6-amino-1-(1H-benzimidazol-2-ylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.28 g, 1.0 mmol, obtained from Example 8(b)) in acetic acid (3 mL) was added, dropwise, a solution of sodium nitrite (0.080 g, 1.1 mmol) in H2O (0.5 mL). The reaction mixture was then stirred for an additional 40 minutes before sodium dithionite (0.36 g, 2.08 g) was added. The resulting mixture was stirred 15 minutes and then evaporated in vacuo. Water (50 mL) was added and the formed solid was collected by filtration, washed with water and dried which gave the title compound (0.19 g, 63%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH:38]([OH:41])([CH3:40])[CH3:39]>>[CH:38]([O:41][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)([CH3:40])[CH3:39]
Reactant: CC(C)O
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: CC(C)Oc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (200 mg, 0.4 mmol) with 2 equivalents each of n-butyl lithium and isopropanol by the procedure described in Reference Examples 6 and 7 to afford the title compound: HPLC/MS: m/e=486 (M++1); Rt=4.11 min. 1H-NMR 400 MD (CDCl3): δ 1.32 (d, J=6 Hz, 6H), 5.01-5.06 (m, 1H), 7.17-7.30 (m, 6H), 7.36-7.37 (d, J=2 Hz, 1H), 7.36-7.41 (m, 1H), 7.56-7.59 (m, 1H), 8.53-8.55 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:13]=[N:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:13]=[N:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)nn1
Reactant: NCCC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1ccc(C(N)=O)nn1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)pyridazine-3-carboxamide (Example 721, Part C) (0.200 g, 0.732 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.0993 g, 0.769 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 10% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fractions containing the product. Take the solid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.154 g, 54%): TOF MS ES+ 387.2 (M+H)+, HRMS calcd for C20H27N4O4 387.2032 (M+H)+, found 387.2024, time 0.52 min; Anal. Calcd for C20H26N4O4: C, 62.16; H, 6.78; N, 14.50. Found: C, 61.58; H, 6.66; N, 14.13.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([NH:16][NH2:17])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]=1>C1(C)C=CC=CC=1>[C:5]1([C:8]2([C:14]3[N:27]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[N:17][N:16]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COC1=NCCCCCC1
Reactant: NNC(=O)C1(c2ccc(Cl)cc2)CCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(C2(c3nnc4n3CCCCCC4)CCCCC2)cc1
Temperature: 120 °C

Procedure:
Anhydrous toluene was added to a mixture of 1-(4-chlorophenyl)cyclohexanecarbohydrazide (62 mg) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (40.1 mg). The reaction vessel was heated to 120° C. overnight, whereupon it was cooled to room temperature and the solvent was evaporated. The crude product was purified by column chromatography to give 3-(1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-α]azocine (2-51) as a white solid.
Reaction SMILES: C1(=O)[N:5]([CH:6]([CH2:18][CH3:19])[C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])=[O:8])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH:6]([CH2:18][CH3:19])[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17])=[O:8]
Reactant: CCC(C(=O)Nc1c(C)cccc1C)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCC(N)C(=O)Nc1c(C)cccc1C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A mixture of 17.7 g (52.6 mmoles) of N-(2-phthalimido-butyryl)-2,6-dimethyl-aniline, 14.2 ml of a 85% aqueous hydrazine hydrate solution and 250 ml of ethanol is boiled for one hour, and then the mixture is processed as described in Example 11. The product is triturated with petroleum ether. 9.45 g of N-(2-amino-butyryl)-2,6-dimethyl-aniline are obtained; m.p.: 48°-49° C. The product is obtained with a yield of 87.1%. The hydrochloride of the compound melts at 213°-214° C. [the melting point reported in the literature (see E. W. Byrnes et al., loc. cit.) is 213.5°-214.5° C⟧
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[S:7][CH:6]2[CH2:8][CH2:9][CH2:10][CH2:11][N:5]2[C:4](=[O:12])[C@H:3]1[NH:13]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2.N1CCCCC1>C(Cl)Cl>[NH2:13][C@H:3]1[C:2]([CH3:1])([CH3:31])[S:7][CH:6]2[CH2:8][CH2:9][CH2:10][CH2:11][N:5]2[C:4]1=[O:12]
Reactant: CC1(C)SC2CCCCN2C(=O)[C@H]1NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC1(C)SC2CCCCN2C(=O)[C@H]1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a round bottom flask was added (9H-fluoren-9-yl)methyl (3R)-2,2-dimethyl-4-oxooctahydropyrido[2,1-b][1,3]thiazin-3-ylcarbamate (37 mg, 0.085 mmol), DCM (1 mL) and piperidine (0.017 mL, 0.17 mmol). The reaction was stirred at rt for 3 hr. The solvent was removed and the residue was dried over vacuum pump overnight to give (3R)-3-amino-2,2-dimethylhexahydropyrido[2,1-b][1,3]thiazin-4(6H)-one (17 mg, 0.080 mmol, 94% yield).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[S:30][C:29]([S:31]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[S:30][C:29]([S:31]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)(=[O:32])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Product: CN1CCN(S(=O)(=O)c2ccc(C#Cc3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)s2)CC1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 1-(5-bromo-thiophene-2-sulfonyl)-4-methyl-piperazine (example B.50) (163 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 69%). MS (EI) 581.1 [(M)+]; mp 226° C.
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH:8]([C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[C:12]=1[NH2:13])([CH3:10])[CH3:9]>C(OCC)C>[CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]([CH:8]([CH3:10])[CH3:9])[C:12]=1[NH:13][C:6]([NH:5][S:2]([Cl:1])(=[O:4])=[O:3])=[O:7])([CH3:20])[CH3:19]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NS(=O)(=O)Cl
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Chlorosulfonyl isocyanate (2.43 g) was dissolved in diethyl ether (10 mL), and at −15° C., the solution was added dropwise to a solution of 2,6-diisopropylaniline in diethyl ether (15 mL). After the mixture was stirred at the same temperature for 1 hour and 30 minutes, the resulting precipitates were collected by filtration and then washed with hexane. Colorless crystals so obtained were dried to afford [[[(2,6-diisopropylphenyl)amino]-carbonyl]amino]sulfonyl chloride (4.11 g). Yield: 75%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[Cl:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][NH:17][C:18]([C:20]2[C:21]([OH:31])=[C:22]3[CH:28]=[C:27]([CH2:29][OH:30])[S:26][C:23]3=[N:24][CH:25]=2)=[O:19])=[CH:14][CH:13]=1>CN(C=O)C.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18]([C:20]2[C:21](=[O:31])[C:22]3[CH:28]=[C:27]([CH2:29][OH:30])[S:26][C:23]=3[N:24]([CH2:8][CH2:9][CH3:10])[CH:25]=2)=[O:19])=[CH:32][CH:33]=1
Reactant: CCCI
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (0.91 g) and 1-iodopropane (0.64 mL) are added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carboxamide (2.0 g, prepared as described in U.S. Pat. No. 6,239,142) in anhydrous DMF (60 mL). The reaction mixture is stirred at room temperature for 4 h. The mixture is diluted with water (150 mL) and filtered. The resulting white powder is washed with water (15 mL) followed by diethyl ether (15 mL) and dried in a vacuum oven to afford 1.73 g of the title compound as a white solid Physical characteristics. Mp 174-175° C. 1H NMR (300 MHz, DMSO-d6) δ 10.62, 8.72, 7.38, 7.29, 5.80, 4.69, 4.55, 4.27, 1.87, 0.89; Anal. Found: C, 58.20; H, 4.96; N. 7.13; Cl, 8.98; S, 8.16.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:18])=[N:7][C:8]([Cl:17])=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Br:19]Br>CC(O)=O>[Br:19][CH2:18][C:6]1[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([Cl:17])[N:7]=1
Reactant: BrBr
Reactant: CCCCc1c(C)nc(Cl)nc1-c1ccccc1
Solvent: CC(=O)O
Product: CCCCc1c(CBr)nc(Cl)nc1-c1ccccc1

Procedure:
A solution of the 5-butyl-2-chloro-4-methyl-6-phenyl-pyrimidine (215 mg, 0.825 mmol) and Br2 (0.042 ml, 0.825 mmol) in AcOH (2 mL) is stirred at 80° C. for 2 hours. After cooling, the solution is concentrated. The residue is partitioned between Et2O and half saturated aqueous NaHCO3. The layers are separated, and the aqueous layer is reextracted once with Et2O. The combined extracts are dried over Na2SO4 and concentrated to 305 mg of crude 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine, which also contains small amounts of SM and dibromo material. This material is used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]([CH:15](O)[CH3:16])[C:13]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:12][N:11]=2)=[CH:6][C:5]=1[CH3:30].O.[OH-].[Li+].O1CCCC1>O>[Cl:29][C:24]1[CH:23]=[C:22]([C:13]2([C:18]([F:20])([F:19])[F:21])[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([CH3:30])[CH:6]=3)[C:14]2=[CH:15][CH3:16])[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2C(C)O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC=C1C(c2ccc(C(=O)O)c(C)c2)=NOC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-[5-(3,5-dichloro-phenyl)-4-(1-hydroxy-ethyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (Example 7.1) (0.242 g, 0.51 mmol), lithium hydroxide monohydrate (0.06 g, 1.4 mmol), tetrahydrofuran (5 ml) and water (5 ml) was stirred at ambient temperature for 2 days. Then further portions of lithium hydroxide monohydrate were added to complete the reaction. In total, 545 mg of lithium hydroxide monohydrate were added over 5 days. The mixture was concentrated and the residue dissolved in water. The solution was acidified by addition of aqueous hydrochloric acid (1N) and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated to give a residue which was used without further purification in the following step. LC-MS showed the presence of 4-[5-(3,5-dichloro-phenyl)-4-ethylidene-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid: RT=2.20 min, m/z=442/444/446 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][CH3:25])=[CH:19][CH:18]=1.C1C(=O)N([Cl:42])C(=O)C1>>[Cl:42][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:24][CH3:25])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: CC[C@@H](c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1)N(C)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Product: CC[C@@H](c1ccc(-c2c(OC)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1)N(C)C(=O)OC(C)(C)C
Yield: 61 %

Procedure:
Following General Procedure H, ((S)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propyl(methyl)carbamate) (200 mg, 0.41 mmol) was reacted with NCS (68 mg, 0.50 mmol) to afford the desired product (130 mg, 61%) as a yellow solid: ESI MS m/z 513 [C27H29ClN2O4S+H]+.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([O:28]CC5C=CC(OC)=CC=5)[CH:23]=4)=[N:17][CH:18]=[CH:19][CH:20]=3)[N:12]=[C:11]([CH3:38])[N:10]=2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>>[NH2:8][C:9]1[N:10]=[C:11]([CH3:38])[N:12]=[C:13]([C:15]2[C:16]([NH:21][C:22]3[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)[N:14]=1
Reactant: COc1ccc(COc2cc(Nc3ncccc3-c3nc(C)nc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)n3)ccn2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2cc[nH]c(=O)c2)n1
Yield: 18.5 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-4-(2-(2-(4-methoxybenzyloxy)pyridin-4-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.120 g, 0.183 mmol) in trifluoroacetic acid (Aldrich) (1.631 mL, 21.96 mmol) and trifluoromethane sulfonic acid (TCI) (0.810 mL, 9.15 mmol) was heated at 80° C. in a sealed tube for 1 h. The reaction mixture was neutralized with sat. NaHCO3. The precipitate was collected by filtration. The precipitate was purified by prep HPLC to give the product as a white solid (0.010 g). m/z (ESI, +ve ion) 296.1 (M+H)+. 1H NMR (300 MHz, d6-DMSO) δ 12.14 (s, 1H); 10.94 (br. s., 1H); 8.81 (d, J=6.87 Hz, 1H); 8.46 (d, J=4.09 Hz, 1H); 7.66-8.04 (m, 2H); 7.24 (d, J=7.31 Hz, 1H); 7.19 (s, 1H); 7.08 (dd, J=7.97, 4.75 Hz, 1H); 6.53 (d, J=5.70 Hz, 1H); 2.44 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.Cl.[F:11][C:12]1([F:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:15]1[CH2:16][CH2:17][C:12]([F:18])([F:11])[CH2:13][CH2:14]1
Reactant: BrCc1cccc(Br)c1
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC1(F)CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
A mixture of 3-bromobenzyl bromide (3.43 g, 13.73 mmol), 4,4-difluoro-piperidine hydrochloride (2.20 g, 13.97 mmol), and potassium carbonate (4.82 g, 34.86 mmol) in acetonitrile (50 mL) was stirred at RT for 16 h. The mixture was filtered and evaporated, and the residue partitioned between water (30 mL) and EtOAc (3×30 mL). The combined organic extracts were washed with water (2×50 mL) and dried (Na2SO4). The solvent was evaporated to give the title compound as a colourless oil (3.96 g, 99%). LCMS (Method 1): Rt 1.89 min, m/z 290/292 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35]>ClCCCl.C1CCN2C(=NCCC2)CC1>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][CH:25]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)[N:1]=[C:34]2[CH3:35])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2cc(Oc3ccccc3)ccc2N)ccc1OCCN1CCCC1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2c(C)nc3ccc(Oc4ccccc4)cc3c2=O)ccc1OCCN1CCCC1
Temperature: 80 °C

Procedure:
A solution of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamide [Example D1] (25 mg, 0.055 mmol) in 1,2-dichloroethane (1 ml) was treated with triethylorthoacetate (2 ml) and the mixture heated to 80° C. for 2 hours. The mixture was cooled, 1 drop of DBU added and the mixture evaporated. The residue was subjected to flash chromatography on silica gel eluting with (methanol-dichloromethane-aqueous ammonia) to give the title compound;
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11]OC)[C:3]=1[CH:4]=[O:5].CC(C)([O-])C.[K+].BrC[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.O>CS(C)=O>[CH:4]([C:3]1[C:2]([OH:1])=[CH:9][CH:8]=[CH:7][C:6]=1[O:10][CH2:11][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)=[O:5]
Reactant: COCOc1cccc(O)c1C=O
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(COc2cccc(O)c2C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-hydroxy-6-methoxymethoxybenzaldehyde (0.91 g, 5.1 mM) in dry dimethyl sulphoxide (8 ml) was added potassium t-butoxide (0.57 g, 5.1 mM) with exclusion of moisture. After 10 mins, ethyl 4-bromomethylbenzoate (1.22 g, 5 mM) was added and the whole stirred at room temperature (18 hrs). The reaction mixture was poured into water (100 ml) and the liberated oil extracted into ether. The combined extracts were washed with 5% sodium carbonate solution, water, dried (sodium sulphate) and evaporated. The residual oil (ethyl 4-(2-formyl-3-methoxymethoxyphenoxymethyl)benzoate was dissolved in ethanol (30 ml) and treated with 3 M hydrochloric acid (30 ml) with stirring at 60° C. (30 mins). The solid was filtered off, washed with water, dried, and recrystallised from ethanol/water to give ethyl 4-(2-formyl-3-hydroxyphenoxymethyl)benzoate, m.p. 105°-ω° C. (identical to a sample previously prepared, Example 5(B)).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[C:5]([Br:13])=[CH:4][N:3]=1.[NH2:14][NH2:15].C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([NH:14][NH2:15])[CH:7]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: NN
Reactant: Nc1ncc(Br)c2cc(F)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NNc1ccc2c(N)ncc(Br)c2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of 1-amino-4-bromo-6-fluoro-isoquinoline (0.1179 g, 0.49 mmol), and hydrazine (0.5 mL) in THF (5 mL) is microwaved at 100° C. for 40 min. Then it is placed in an oil bath and is stirred at 100° C. for 16 h. The reaction mixture is cooled to RT. It is treated with NaHCO3 (satd. aq, 10 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum to afford 0.079 g (64%) of 4-Bromo-6-hydrazino-isoquinolin-1-ylamine. LC/MS m/z=254 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[N:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:25][NH:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH:27]1([N:26]([CH3:25])[C:19]2[N:18]=[C:17]([N:14]3[CH2:15][CH2:16][CH:11]([C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:2])=[O:24])=[CH:10][CH:9]=4)[CH2:12][CH2:13]3)[CH:22]=[CH:21][N:20]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)Cc1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Reactant: CNC1CCCC1
Solvent: CC#N
Product: CN(c1nccc(N2CCC(c3ccc(CC(=O)O)cc3)CC2)n1)C1CCCC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To 2.70 g (7.81 mmol) {4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-acetic acid methyl ester (XII.2) in 20 mL ACN are added 2.64 mL (23.4 mmol) N-methyl-cyclopentylamine. The mixture is stirred for 2 h at 150° C. under microwave irradiation. After that time, the solvent is evaporated, the residue taken up in 60 mL ethanol and 30 mL 1N NaOH are added. The mixture is stirred for 1 h at rt and for 1 h at 40° C. Subsequently, 30 mL 1N HCl are added, the mixture is concentrated in vacuo and extracted with DCM. The organic layer is dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silica gel; DCM:EtOH 80:20) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:21])=[C:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:6]=1[C:7](O)=[O:8].[NH2:22][C:23]1([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([C:23]2([NH:22][C:7]([C:6]3[C:5]([CH2:10][C:11]4[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=4)=[C:4]([CH3:21])[S:3][C:2]=3[CH3:1])=[O:8])[CH2:25][CH2:24]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: Cc1sc(C)c(C(=O)O)c1Cc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(C2(N)CC2)cc1
Product: Cc1sc(C)c(C(=O)NC2(c3ccc(C#N)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
2,5-Dimethyl-4-[4-(trifluoromethyl)benzyl]thiophene-3-carboxylic acid from Example 11, Step 4 (286 mg, 0.910 mmol) was reacted with 4-(1-aminocyclopropyl)benzonitrile from Example 14, Step 1 (144 mg, 0.910 mmol) under conditions similar to Example 1, Step 10. The crude product was purified by Combi Flash chromatography system (2-5% EtOAc/CHCl3 in 20 min.) to afford the desired product as a pale yellow solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[O:16]>OS(O)(=O)=O>[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: O=S(=O)(O)O
Product: Cc1cc2c(c([N+](=O)[O-])c1)NC(=O)C2=O
Reaction time: 0.12 h

Procedure:
Fuming nitric acid (10 mL) was added drop wise over a period of 30 min to a solution of 5-methyl-1H-indole-2,3-dione (20 g, 0.124 mol) in conc. H2SO4 (80 mL) at −5° C., utes. The reaction mass was stirred for another 5-10 min at the same temperature and was poured into crushed ice. The precipitate was filtered and washed with chilled water several times. Finally it was dried in a vacuum oven to get 6.5 g of the required product as a yellow coloured solid.