Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:10]C(=O)OC.C1(C)C=CC(S(O[CH:25]2[CH2:29][CH2:28][CH2:27][CH:26]2[CH3:30])(=O)=O)=CC=1.[OH-].[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:25]2[CH2:29][CH2:28][CH2:27][CH:26]2[CH3:30])=[CH:4][C:3]=1[NH2:10]
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2C)cc1
Reactant: COC(=O)Nc1cc(O)c(Cl)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1CCCC1Oc1cc(N)c(F)cc1Cl
Temperature: 90 °C
Reaction time: 7 h
Yield: 40 %

Procedure:
A solution of methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (1.53 g, 6.98 mmol) synthesized by the process described in Reference Example 8, 2-methylcyclopentyl p-toluenesulfonate (1.78 g, 6.99 mmol) and N,N-dimethylformamide (15 ml) was charged into a 50 cc round-bottom flask, and then potassium hydroxide (400 mg, 7.15 mmol) in a powder form was added thereto, followed by stirring for 7 hours while heating on an oil bath at 80 to 100° C. After completion of the reaction, the reaction solution was cooled to room temperature, 2N hydrochloric acid (50 ml) was added thereto, and the mixture was extracted with ethyl acetate (20 ml×8). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product (1.51 g). The product was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=17/3) to obtain 2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyaniline as a colorless oily substance (668 mg, 2.73 mmol, 40% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1coc(-c2ccc(Cl)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1coc(-c2ccc(Cl)cc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 10 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)oxazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (14 mgs, 10% yield). 1H NMR (CDCl3) δ 9.45 (s, 1H), 9.29 (s, 1H), 8.84 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 3.85 (d, J=5.1 Hz, 2H), 2.93 (t, J=5.4 Hz, 2H). MS (ESI) m/z: Calculated for C20H13ClF3N5O3: 463.07. found: 464.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:15][OH:16].CCN(CC)CC>C1COCC1>[CH3:15][O:16][C:8](=[O:9])[C:7]([O:6][C:5]1[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)Cl
Reactant: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
2-(4-Bromophenoxy)-2-methylpropanoyl chloride (2.34 g, 8.4 mmol) in THF (10 mL) was added dropwise whilst stirring to anhydrous MeOH (1.34 g, 42 mmol), Et3N (1.7 g, 16.8 mmol) and THF at 0° C. The mixture was stirred at room temperature for 3 h, concentrated and distilled to afford the sub-title compound (1.74 g, 97%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[NH:11][C:10]2([CH3:18])[CH3:17].O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[NH:11][C:10]2([CH3:18])[CH3:17]
Reactant: COc1ccc2c(c1)C(C)(C)NC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)NC(=O)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
A 1 M solution of BBr3 in CH2Cl2 (88.0 mL, 88.0 mmol) is dissolved in dry CH2Cl2 under N2. A solution of lactam 57 (7.65 g, 40.0 mmol) in CH2Cl2 (50 mL) is added to the BBr3 solution dropwise over 10 min. The resulting mixture is stirred at rt overnight. The reaction mixture is poured into water and extracted with EtOAc (3×). The organic phase is dried (MgSO4), filtered, and evaporated, leaving the product 62 as a white solid (4.03 g, 57%), mp 231-233° C., which requires no purification. 1H NMR (DMSO-d6, 2.50 ppm) 8.18 (s, 1), 7.28 (d, 1, J=8.5), 6.75 (d, 1, J=1.6), 6.67 (dd, 1, J=8.5, 1.6), 1.25 (s, 6); 13C NMR (CDCl3 +DMSO-d6) 169.30, 161.06, 155.40, 124.68, 121.53, 115.39, 107.26, 57.98, 27.47; MS (MW=177.2, EI, eE=70 eV) m/z 177 (M+), 163, 162 (base peak).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
In methanol (10 ml) was dissolved ethyl N-tert-butoxycarbonyl-4-piperidylideneacetate (1.20 g) followed by addition of palladium-on-carbon (180 mg). After nitrogen purging, hydrogen gas was introduced and the mixture was stirred at room temperature for 2 hours. The catalyst was then filtered off and the filtrate was concentrated to provide the title compound as white powder (1.18 g). 1H-NMR (CDCl3) δ: 1.1-1.3(2H,m), 1.26(3H,t,J=7.2Hz),1.45(9H,s), 1.6-2.0(3H,m), 2.23(2H,d,J=7.OHz), 2.72(2H,t,J=12.0Hz), 4.0-4.1(2H,m), 4.13(2H,q,J=7.2Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1/[CH:4]=[N:5]/[OH:6].[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([Cl:12])=[N:5][OH:6]
Reactant: O/N=C/c1c(F)cccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1c(F)cccc1Cl
Temperature: 25 °C
Yield: 697.8 %

Procedure:
To a solution of (E)-2-chloro-6-fluorobenzaldehyde oxime (2 g) in 10 mL Dimethylformamide (DMF) at room temperature 0.23 g N-Chlorosuccinimide (NCS) were added. Dry hydrogen chloride was bubbled into the DMF solution until the reaction temperature rise up to 35° C. Then 1.21 g N-chloro-succinimide were added in portions, the temperature was kept at 35-45° C. The reaction mixture was cooled to room temperature and poured into 30 mL ice and extracted with ether. Combined extracts were dried and evaporated to give 2.5 g of 2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride as a yellow oil.
Reaction SMILES: C([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16])C1C=CC=CC=1>CO.[Pd]>[C:19]12([CH2:18][O:17][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@H:10]3[C:9]([OH:29])=[O:8])=[O:16])[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]3)[CH2:28]1)[CH2:26]2
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)OCC12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of N-[(1-adamantyl)methoxycarbonyl]-L-proline benzyl ester (1.98 g) in methanol (60 ml) was added 10% Pd-C (0.20 g), and the mixture was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The catalyst was filtered off, and the filtrate was concentrated to give 1.53 g of the title compound.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)C.[BrH:10].[CH3:11][C:12]([OH:14])=O>>[BrH:10].[Br:10][CH2:11][C:12]([C:7]1[CH:6]=[N:5][CH:4]=[CH:9][CH:8]=1)=[O:14]
Reactant: CC(=O)c1ccccn1
Reactant: CC(=O)O
Agent: Br
Product: O=C(CBr)c1cccnc1
Temperature: 60 °C

Procedure:
Acetylpyridine (120 g) is added to 33% HBr/AcOH (600 ml) with stirring (If the salt precipitates more AcOH, up to 800 ml may be added). Bromine (176 g) is added and the reaction mixture is heated to 60° C. for 2-3 h. The reaction mixture is cooled and ether (1400 ml) is added. The solid is filtered, washed with ether, and dried to give 2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (Compound 13), in quantitative yield
Reaction SMILES: C(N)(=S)C1C=CC=CC=1.[CH2:10]([C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[CH:25][CH:24]=1)[CH3:11].[CH2:34]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37]>>[CH2:10]([C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:38]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=1)[CH3:11]
Reactant: CCc1sc(-c2ccccc2)nc1-c1ccc(OCCCCl)cc1
Reactant: CCCCNCCCC
Agent: NC(=S)c1ccccc1
Product: CCCCN(CCCC)CCCOc1ccc(-c2nc(-c3ccccc3)sc2CC)cc1

Procedure:
The title compound was prepared according to Example 1, using p-hydroxybutyrophenone (20 g, 0.12 mol) in place of p-hydroxyacetophenone and 1-bromo-3-chloropropane (48 ml, 0.48 mol) to give 25 g (85% yield) of p-chloropropoxybutyrophenone as an oil. 1H NMR (CDCl3): δ7.92 (d, J=8.9 Hz, 2H), 6.91 (d, J=8.9 Hz, 2H), 4.15 (t, J=5.9 Hz, 2H), 3.73 (t, J=6.3 Hz, 2H), 2.87 (t, J=7.0 Hz, 2H), 2.23 (m, 2H), 1.78 (m, 2H), 0.99 (t, J= 7.0 Hz, 3H). Bromination (5 ml, 0.10 mol) followed by condensation with thiobenzamide (10 g, 73 mmol) of this product as described in Example 1 afforded 5-ethyl-4-(4-chloropropoxyphenyl)-2-phenylthiazole in 48% yield (15 g) as a white solid, mp 117°-119° C. Treatment of this product (5.1 g, 11 mmol) with dibutylamine in accordance with Example 1 gave 4.4 g (83% yield) of the free base of the title compound which was converted to the HCl salt, mp 128°-131° C. IR(KBr): 3400, 2610, 1620 cm-1, MS: 451(MH+). 1H NMR (CD3OD): δ7.96-7.02 (m, 9H), 4.12 (t, J=5.8 Hz, 2H), 3.38-2.76 (m, 8H), 2.20 (m, 2H), 1.75-1.18 (m, 14H), 0.91 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([C:27]4[C:32]([CH3:33])=[CH:31][C:30]([O:34][Si](C(C)(C)C)(C)C)=[CH:29][C:28]=4[CH3:42])[C:21]([C:25]#[N:26])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([C:27]4[C:32]([CH3:33])=[CH:31][C:30]([OH:34])=[CH:29][C:28]=4[CH3:42])[C:21]([C:25]#[N:26])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C#N)c3-c2c(C)cc(O[Si](C)(C)C(C)(C)C)cc2C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C#N)c3-c2c(C)cc(O)cc2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
(1S,2S)-2-(4-{(R)-4-[4-(tert-Butyl-dimethyl-silanyloxy)-2,6-dimethyl-phenyl]-5-cyano-indan-1-yloxy}-phenyl)-cyclopropanecarboxylic acid ethyl ester (500 mg, 0.86 mmol) is dissolved in 10 mL of tetrahydrofuran, a 1 M aqueous solution of tetrabutylammonium fluoride (2 mL, 2.00 mmol) is added and the reaction mixture is stirred at room temperature for 3 h. 2 mL of an ammonium chloride saturated aqueous solution is added and the reaction mixture is concentrated under vacuum. The crude product obtained is purified by flash chromatography (cyclohexane/ethyl acetate 100/01→50/50) to give the title compound (Yield: 310 mg).
Reaction SMILES: [CH3:1][N:2]([CH:21]1[C:29]2[C:24](=[C:25]([OH:30])[CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][C:4]1[O:5][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH:21]1[C:29]2[C:24](=[C:25]([O:30][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][C:4]1[O:5][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:8]=1
Reactant: CCOC(=O)CBr
Reactant: CN(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCC2N(C)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 24 h
Yield: 60.3 %

Procedure:
To a solution of 1-[N-methyl-N-[(4,5-diphenyloxazol-9-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (109 mg) in dichloromethane (2 ml) was added 1M boron tribromide dichloromethane solution (1 ml) at 0° C. After being stirred for 4 hours at 0° C., the solvent was evaporated in vacuo. The residue was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo to afford crude 1-[N-methyl-N-[4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-hydroxy-1H-indene (109 mg). To a solution of crude 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-hydroxy-1H-indene (109 mg) and ethyl bromoacetate (80 mg) in DMF (3 ml) was added K2CO3 (80 mg). After being stirred for 24 hours, the solution was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated on vacuo. The residue was purified by chromatography on silica gel to afford 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-ethoxycarbonylmethoxy-1H-indene (80 mg) MS (m/z): 483 (M+ +1) NMR (CDCl3, δ): 1.29 (3H, t, J=7.1 Hz), 1.98-2.21 (2H, m), 2.41 (3H, s), 2.75-3.18 (2H, m), 3.78 (1H, d, J=12 Hz), 3.82 (1H, d, J=12 Hz), 4.25 (2H, q, J=7.1 Hz), 4.63 (2H, s), 4.55-4.65 (1H, m), 6.62 (1H, m), 7.15-7.18 (2H, m), 7.25-7.45 (6H, m), 7.60-7.75 (4H, m)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1)[C:9](=[O:32])[NH:10][C@H:11]([C:20](=[O:31])[NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[O:30])[CH2:28][CH3:29])[N:26]=1)[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@H:8]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1)[C:9]([NH:10][C@@H:11]([C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:20]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[O:30])[CH2:28][CH3:29])[N:26]=1)=[O:31])=[O:32]
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OCCN3CCOCC3)cc2)[C@@H](C)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCOCC3)cc2)[C@@H](C)c2ccccc2)n1
Reaction time: 2 h

Procedure:
{(R)-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-[(1S,2S)-2-phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl]-methyl}-carbamic acid-tert-butyl ester (0.19 mmol) was dissolved in a 30% v/v solution of trifluoroacetic acid in dichloromethane (5 mL) at 0° C. After stirring for 2 hours the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was adjusted to pH=8 by the addition of solid sodium bicarbonate. The aqueous layer was again extracted with ethyl acetate (2×). The combined organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to give crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide which was used immediately and without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[C:17]3[N:19]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[N:20]=[C:21]([CH3:22])[C:16]3=[C:15]([CH2:29][N:30]3[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][CH2:32][C:31]3([CH3:39])[CH3:38])[CH:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44]>C1COCC1>[CH3:40][O:41][CH2:42][C:43]([N:33]1[CH2:32][C:31]([CH3:39])([CH3:38])[N:30]([CH2:29][C:15]2[CH:14]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=3)[N:18]=[C:17]3[N:19]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[N:20]=[C:21]([CH3:22])[C:16]=23)[CH2:35][C:34]1([CH3:37])[CH3:36])=[O:44]
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reactant: COCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(-c2cc(CN3CC(C)(C)N(C(=O)COC)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Yield: 102.4 %

Procedure:
To 16 mg sodium hydride (60% in mineral oil) in 2 ml of abs. THF were added 80 mg of 6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine and after 10 min 17 mg of 2-methoxyacetyl chloride were added. After 16 h at rt the reaction was quenched by the addition of water, the layers were separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried and concetrated in vacuo. 93 mg of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.[C:29]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:29]([O:33][C:34](=[O:35])[C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[CH:9][N:8]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=4)(=[O:20])=[O:21])[C:5]3=[N:6][CH:7]=2)[CH:41]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Temperature: 90 °C
Yield: 87.3 %

Procedure:
To a solution of 5-bromo-3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.01 g, 2.21 mmol) in a 1:1 acetonitrile/saturated aqueous NaHCO3 solution (20 mL total) was added (3-tert-butoxycarbonylphenyl)boronic acid (0.54 g, 2.43 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (0.90 g, 0.11 mmol) in a microwave vial. The vial was capped, flushed with N2, evacuated under vacuum, and subsequently heated in a microwave at 90° C. for 1800 seconds. The material was diluted with ethyl acetate and the organic layer was washed with H2O then dried over Na2SO4. The solution was adsorbed onto silica gel and purified by flash chromatography with a gradient of ethyl acetate and hexanes, affording 3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-benzoic acid tert-butyl ester as a white solid (1.07 g, 87% yield). 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 8.17 (br s, 3H), 8.09 (s, 1H), 7.99 (m, 2H), 7.71 (d, J=6.5 Hz, 1H), 7.50 (m, 2H), 7.34 (t, J=8.0 Hz, 1H), 7.32 (d, J=6.5 Hz, 2H), 7.06 (m, 2H), 3.88 (s, 3H), 2.39 (s, 3H), 1.60 (s, 9H). MS: m/e 555.1 (M+H+).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[CH2:9](N)[C:10]1[O:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>O>[CH2:9]([NH:6][C:5]1[CH:7]=[CH:8][NH:1][C:2](=[O:3])[N:4]=1)[C:10]1[O:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccco1
Reactant: Nc1cc[nH]c(=O)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: O=c1nc(NCc2ccco2)cc[nH]1
Reaction time: 72 h
Yield: 88.9 %

Procedure:
To the reaction flask with 40 g cytosine (0.36 mol), 190 ml furfurylamine (6 mol) (FIG. 1 IV and V), the same amount of water and 5.67 g catalyst ammonium chloride (0.3 mol) was added. The mixture was heated till boiling within 48-96 h. After cooling, the mixture was extracted with dichloromethane (ca. 300 ml). The organic layer was filtered to isolate the product. The raw product was crystallized and 61.196 g of pure product was obtained with yield 89%.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[S:27])[N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.CN>>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[S:27])[N:24]([CH3:25])[CH3:26])=[CH:18][CH:17]=1
Reactant: CN(C)C(=S)Oc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: CN
Product: CN(C)C(=S)Oc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
A mixture of dimethylthiocarbamic acid O-{4-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-butyl]phenyl}ester 9 (0.30 g, 0.80 mmol) and methylamine (2M in methanol, 10 mL, 20 mmol) was stirred at room temperature overnight. Solvent was removed by rotary evaporation and the residue was purified by flash silica gel column chromatography (Biotage) eluting with chloroform/methanol/concentrated ammonium hydroxide (10:1:0.1, v/v) to give dimethylthiocarbamic acid O-[4-(4-aminobutyl)phenyl]ester (10) as a clear colorless oil (118 mg, 46% yield). 1H NMR (300 MHz, CD3OD) δ 1.70 (m, 4H), 2.70 (m, 4H), 3.34 (s, 3H), 3.46 (s, 3H), 6.96 (d, 2H), 7.20 (d, 2H). m/z (ESI): 253 [C13H20N2OS+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Br:14]Br.C(C1C=CC=CC=1)(=O)C>C(O)(=O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9](=[O:11])[CH2:10][Br:14]
Reactant: BrBr
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(CBr)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
m-(Trifluoromethyl)acetophenone (10 g, 0.054 mol) was dissolved in 100 ml acetic acid. Bromine (9.1 g, 0.057 mol) was separately dissolved in 20 ml acetic acid and added portionwise over 0.5 hours to the acetophenone solution. The mixture was stirred for 15 hours, poured onto 150 g ice and extracted with 300 ml ether. The organic layer was washed 1×300 ml H2O, 1×300 ml saturated NaCl, dried (MgSO4) and evaporated to yield title product as a pale yellow liquid.
Reaction SMILES: [NH:1]([CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH:1]([CH:8]1[CH2:12][CH2:11][N:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(NC2CCNC2)cc1
Reactant: BrCCc1ccccc1
Product: c1ccc(CCN2CCC(Nc3ccccc3)C2)cc1

Procedure:
3-Anilinopyrrolidine and 2-bromoethylbenzene are reacted under the same conditions as in Starting Material Synthetic Example 4 to give 3-anilino-1-(2-phenylethyl)pyrrolidine.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(O)C.[Pd]>[N:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)=[CH:2][N:3]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc(Cl)nnc2Cl)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cccc(-c2ccnnc2)c1
Yield: 88 %

Procedure:
A suspension of 3,6dichloro4-(3-nitro-phenyl)pyridazine (0.19 g) and sodium hydrogen carbonate (147 mg) in tetrahydrofuran (2 ml) and ethanol (5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 100 mg) under hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated. The residue was diluted with ethyl acetate and an aqueous solution of sodium hydrogen carbonate. The separated organic layer was washed with brine and dried over potassium carbonate. The organic layer was evaporated under reduced pressure to give 3-(pyridazin-4-yl)phenylamine (106 mg, 88.3%).