Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(C(N)=O)[CH2:11][C:10]([O:14][CH3:15])([O:12][CH3:13])[CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.C1([I+2])C=CC=CC=1.[Na].C(#[N:43])C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:43])[CH2:11][C:10]([O:14][CH3:15])([O:12][CH3:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC1(OC)CC(C(N)=O)(c2ccc(Br)cc2)C1
Reactant: CC#N
Agent: O=C([O-])C(F)(F)F
Agent: [I+2]c1ccccc1
Agent: [Na]
Solvent: O
Product: COC1(OC)CC(N)(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(4-bromophenyl)-3,3-dimethoxycyclobutanecarboxamide (2.3 g, 7.32 mmol) in acetonitrile (9 ml) and Water (9.00 ml) was added phenyliodine bis(trifluoroacetate) (4.73 g, 11.00 mmol) and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was slowly poured into sodium bicarnate sat. solution (˜45 ml) and extracted with ethyl acetate (3×30 ml). The combined organic phase was washed with water, brine and concentrated to give crude product (3.4 g). The crude product was purified by column (biotage, 50 g) eluted with 0-5% DCM/Methanol (mixture of 500 ml methanol and 60 ml 2M NH4OH in methanol) to give product 1-(4-bromophenyl)-3,3-dimethoxycyclobutanamine (1.06 g), 1H NMR (500 MHz, CDCl3): 7.48 (d, 2H), 7.32 (d, 2H), 3.27 (d, 3H), 3.17 (d, 3H), 2.66 (d, 2H), 2.44 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl>N1C=CC=CC=1>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
10 g 4-hydroxybenzoic acid was dissolved in 50 ml dry pyridine. The solution was then externally cooled with ice water while 10.5 g hexanoyl chloride was added dropwise. After the resultant mixture had been further stirred overnight at room temperature, it was poured in 300 ml 3-N dilute hydrochloric acid. White precipitate was taken up by filtration. By recrystallizing the white precipitate in a mixed solvent of methanol/water (3:2), 14.8 g 4-hexanoyloxybenzoic acid was obtained in 87% yield based upon the amount of the hydroxybenzoic acid.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:3]1[OH:23].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O>>[OH:23][C@H:3]1[C@@H:2]([O:1][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCCOCCO
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Product: COCCOCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O

Procedure:
350 mg of the title compound are obtained by column chromatographic purification on silica gel (eluent: diethyl ether/2-propanol=10/1) of the crude product from the above reaction of (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine with 2-(2-methoxyethoxy)ethanol. 1H-NMR (200 MHz, DMSO): δ=2.26 (s, 3H), 2.33 (s, 3H), 3.23 (s, 3H), 3.39-4.01 (m, 8H), 3.59-3.69 (m, 2H), 4.25-4.26 (d, 1H), 4.45-4.50 (m, 1H), 4.64-4.68 (d, 1 OH), 5.94-5.95 (d, 1 NH), 6.76-6.79 (d, 1H), 7.24-7.44 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([NH:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:27])[CH:3]=1.O[Li].O>CO.O>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:23])([CH3:24])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])[CH:3]=1
Reactant: COC(=O)CNC(=O)c1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)NCC(=O)O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
A mixture of methyl 2-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]formamido}acetate (90) (0.13 g, 0.27 mmol) and LiOH.H2O (0.07 g, 2 mmol) in MeOH (10 mL) and water (10 mL) was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the aqueous residue was acidified with 1 M HCl. The resulting solid was collected by filtration to give 2-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]formamido}acetic acid (91) (0.09 g, 72%) as a brown solid. 1H NMR (CD3OD): δ 8.82 (m, 1H), 7.24 (d, 1H), 7.03 (d, 1H), 4.06 (m, 2H), 3.47 (m 2H), 2.76 (d, 1H), 2.11 (d, 1H), 1.88-1.38 (m, 10H), 1.20 (m, 1H), 1.00 (m, 5H), 0.89 (s, 3H), 0.86 (s, 3H). MS m/z 464 (C24H33NO6S+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[N:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[C:17]=23)[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[C:36]([NH2:39])(=[O:38])[CH3:37].CNCCNC>O1CCOCC1.[Cu]I>[NH2:22][C:18]1[C:17]2[N:16]([C:15]([CH:23]3[CH2:26][CH2:25][CH2:24]3)=[N:14][C:13]=2[C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:39][C:36](=[O:38])[CH3:37])[CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4cccc(Br)c4)c3)c12
Reactant: CC(N)=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)c1
Temperature: 170 °C

Procedure:
Argon was bubbled through a suspension of 1-[3-(3-bromobenzyloxy)-phenyl]-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine (1, 25 mg, 0.056 mmol), potassium carbonate (15 mg, 0.109 mmol), copper(I) iodide (10 mg, 0.052 mmol), acetamide (40 mg, 0.68 mmol) and N,N′-dimethylethylenediamine (5 mg, 0.057 mmol), in dioxane (0.5 ml) in a thick walled 5 ml microwave tube. The tube was sealed and heated to 170° C. for 2 hours using the CEM Discover microwave oven at a maximum power of 250 W. The reaction mixture was then partitioned between water (3 ml) and ethyl acetate (3 ml) and the aqueous layer was extracted with further ethyl acetate (2×3 ml). The combined organic extracts were washed with water (2×3 ml) and brine (3 ml) then evaporated in vacuo. The residues after evaporation were dissolved in methanol and loaded on to 1 g SCX cartridges, then eluted with methanol and methanol/ammonia (concentrated aqueous ammonia in methanol, 3% v/v). Fractions containing product were combined and evaporated to furnish N-{3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-phenyl}-acetamide as an off white solid (10 mg, 0.023 mmol, 42%, 85% pure). This was purified further using preparative mass directed HPLC purification (conditions) to afford 2 as an off white solid (6.3 mg, 0.015 mmol, 27%; (M+H)+ m/z 428.2; Retention Time; 2.87 min; 1H-NMR (D4-MeOH) δ 7.72 (1H, br t), 7.53 (1H, br d, J=8 Hz), 7.49 (1H, t, J=8 Hz), 7.43 (1H, d, J=5.1 Hz), 7.35 (1H, t, 7.8 Hz), 7.29 (1H, br t), 7.25-7.22 (2H, m), 7.17 (1H, dd, J=2.8, 8.2 Hz), 7.01 (1H, d, J=5.1 Hz), 5.21 (2H, s), 4.00 (1H, p, J=8.4 Hz), 2.55 (4H, m), 2.22 (1H, m), 2.15 (3H, s), 2.10-2.02 (1H, m).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([CH:15]([F:17])[F:16])=[N:13][CH:14]=2)([CH3:8])[C:6]#[N:7])[CH2:3][CH2:2]1.N.O.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[Ni]>[CH:1]1([CH2:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([CH:15]([F:16])[F:17])=[N:13][CH:14]=2)([CH3:8])[CH2:6][NH2:7])[CH2:3][CH2:2]1
Reactant: CC(C#N)(CC1CC1)c1cnc(C(F)F)nc1
Agent: [Ni]
Agent: N
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: O
Product: CC(CN)(CC1CC1)c1cnc(C(F)F)nc1
Yield: 98.7 %

Procedure:
A mixture of 3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropanenitrile (1 g, 4.2 mmol) and NH3.H2O (3 mL) in MeOH (20 mL) was hydrogenated with Raney Ni (1.5 g) under 50 Psi for 3 h. The reaction mixture was filtered and concentrated to give 3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropan-1-amine (1 g), which was used directly for next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:38][C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NC4CCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and cyclobutylamine. ES-MS m/e (%): 440 (M+H+, 100).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]2[O:15][N:14]=[CH:13][C:12]=2[C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[C:18]=2[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:10][CH2:9]1>ClCCl>[C:13]([CH:12]([C:11]([CH:8]1[CH2:9][CH2:10]1)=[O:15])[C:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[C:18]=1[S:25]([CH3:28])(=[O:26])=[O:27])=[O:29])#[N:14]
Reactant: CS(=O)(=O)c1c(C(=O)c2cnoc2C2CC2)ccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1c(C(=O)C(C#N)C(=O)C2CC2)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (0.5 ml) was added to 5-cyclopropyl-4-(3,4-dichloro-2-methylsulphonylbenzoyl)isoxazole (1.0 g) in dichloromethane. The mixture was stirred at room temperature for 2.5 hours and evaporated to dryness. The residue was suspended in hydrochloric acid (2M) and was extracted with dichloromethane. The organic layer was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 2-cyano-3-cyclopropyl-1-(3,4-dichloro-2-methylsulphonylphenyl)propan-1,3-dione (COMPOUND 623) as a white solid, m.p. 88°-90° C.45
Reaction SMILES: N(CCO)(CCO)CCO.[CH:11](=[O:17])[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1.[C:18](#[N:21])[CH:19]=[CH2:20]>CN(C)C=O.C(O)C>[O:16]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:11]([CH:19]([CH3:20])[C:18]#[N:21])=[O:17]
Reactant: O=Cc1ccco1
Reactant: C=CC#N
Solvent: CN(C)C=O
Solvent: CCO
Solvent: OCCN(CCO)CCO
Product: CC(C#N)C(=O)c1ccco1
Reaction time: 0.5 h

Procedure:
Following the procedure in Example 1, 29.8 g. (0.2 mol) of triethanolamine are added to 48 g (0.5 mol) of furfuraldehyde and 13.5 g of Catalyst 1 (0.05 mol) in a mixture of 300 ml of dimethylformamide and 300 ml of ethanol and the whole is then brought to the reflux temperature while stirring under a stream of nitrogen. After 30 minutes, the dropwise addition of a solution of 26.5 (0.05 mol) of distilled acrylonitrile in a mixture of 50 ml of dimethylformamide and 50 ml of ethanol, over the course of 41/2 hours, is started. The mixture is then kept at the same temperature for 20 hours. The solvent mixture is distilled off and the residue is taken up in 300 ml of chloroform. The chloroform solution is then washed with water, dilute sodium bicarbonate solution and twice more with water. It is then dried with magnesium sulphate and after filtering the solution the solvent is distilled off. The residue which remains is distilled in an oil pump vacuum. The α-furoylpropionitrile thus obtained is recrystallized from isopropanol.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH2:42]O>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:14](=[O:23])[N:13]([CH2:42][C:38]3[N:37]([CH3:36])[CH:41]=[CH:40][N:39]=3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NC(=O)N2c1ccccc1Cl
Reactant: Cn1ccnc1CO
Product: Cn1ccnc1CN1C(=O)N(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=614.1 (M+H+), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 1-methylimidazole-2-methanol.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH2:13][N:14]2[C@@H:18]([CH3:19])[C@@H:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[O:16][C:15]2=[O:34])=[N:11][CH:10]=[CH:9][N:8]=1)(=O)=O.[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([F:47])=[C:42](B(O)O)[CH:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:25]=[C:20]([C@H:17]2[O:16][C:15](=[O:34])[N:14]([CH2:13][C:12]3[C:7]([C:42]4[CH:43]=[C:38]([Cl:37])[CH:39]=[CH:40][C:41]=4[F:47])=[N:8][CH:9]=[CH:10][N:11]=3)[C@H:18]2[CH3:19])[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nccnc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nccnc1-c1cc(Cl)ccc1F

Procedure:
3-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrazin-2-yl trifluoromethanesulfonate (Step D, 80 mg, 0.145 mmol), (5-chloro-2-fluorophenyl)boronic acid (30.3 mg, 0.173 mmol), Cs2CO3 (118 mg, 0.361 mmol), 1,1′-bis(diphenylphosphino) ferrocene-palladium dichloride dichloromethane adduct (11.81 mg, 0.014 mmol) and 1,4-dioxane (1 mL) were sealed in a microwave vessel and subjected to microwave irradiation at 140° C. for 25 min. LCMS indicated formation of the desired product. The crude mixture was diluted with MeCN and filtered. The filtrate was purified by preparative HPLC (Kromasil 100-5C 18, 100×21.1 mm) eluting with MeCN/water+0.1% TFA (10% to 100% organic in 10 min, hold 100% in 2 min, 20 mL/min). Related fractions were pooled and evaporated in vacuo to afford an aqueous mixture. The resulting aqueous mixture was extracted with EtOAc, washed with aqueous NaHCO3, dried (Na2SO4), filtered and concentrated to afford a brown glass as the titled compound. LCMS calc.=533.07; found=534.19 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][CH2:6][OH:7].[CH3:12][N:13]=[C:14]=S.CI.CCOCC>CO>[OH:7][CH2:6][CH2:5][N:4]1[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:12]1[NH:13][CH3:14]
Reactant: CN=C=S
Reactant: Nc1ccccc1NCCO
Solvent: CI
Solvent: CCOCC
Solvent: CO
Product: CNc1nc2ccccc2n1CCO
Temperature: 0 °C
Yield: 21.4 %

Procedure:
According to the procedure of B. Agai, et al., Tetrahedron, 32, 839, (1976), to a cooled (0° C.), stirred suspension of 2-(2-aminoanilino)ethanol (30.4 g, 0.200 mol) in MeOH (100 mL) was added a solution of CH3NCS (14.6 g, 0.200 mol) in MeOH (60 mL) dropwise. The resulting mixture was stirred at room temperature for 4 hours and then heated under reflux for 15 minutes. CH3I (28.4 g, 0.200 mol) was added and the mixture was heated under reflux for 10 minutes, cooled to room temperature and stirred for 2 hours. Ether (200 mL) was added and the resulting precipitate was collected by filtration, taken up in nBuOH (140 mL), and heated under reflux for 10 hours. The mixture was cooled in the freezer for 3 hours and the white crystals were filtered. The material was dissolved in H2O and the solution was neutralized with 10% aqueous K 2 CO3. The white solid was collected by filtration to give 8.2 g (21%) of product m.p. >200° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]([CH2:22][CH2:23][O:24]C(=O)C)[CH2:5]1)(=O)C.[OH-].[Na+]>O>[OH:24][CH2:23][CH2:22][CH:6]1[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[C:10]([CH3:20])=[CH:9][C:8]=2[CH3:21])[NH:4][CH2:5]1
Reactant: CC(=O)OCCC1CN(C(C)=O)c2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCO
Temperature: 60 °C
Reaction time: 10 h
Yield: 51.6 %

Procedure:
N-[1-Acetyl-3-(2-acetoxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (4.0 g) was dissolved in ETOH (40 ml) and a solution of NaOH (2.2 g) in water (10 ml) was added, which was followed by stirring at 60° C. for 10 hr. EtOH was evaporated under reduced pressure, and CHCl3 (100 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 1.6 g of N-[3-(2-hydroxyethyl)-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:10][CH2:9][C:8]2[N:11]=[CH:12][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH2:6]1)=[O:4].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:11]=[CH:12][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)C1Cc2c(ncn2Cc2ccccc2)CN1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(cn1)ncn2Cc1ccccc1
Temperature: 0 °C
Yield: 34 %

Procedure:
A solution of H-His-(Bzl)-OH (2.0 g, 8.16 mmol) and formaldehyde (37% in water, 0.92 ml, 12.24 mmol) in water (16 ml) was heated to reflux for 4 hours and concentrated to dryness. The residue was dissolved in methanol (4.6 ml) cooled to 0° C. and treated with thionyl chloride (0.6 ml, 8.12 mmol). The reaction mixture was reflux for 2.5 hours and concentrated. The solid was dissolved in dichloromethane, washed with a saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and concentrated to dryness to yield 1-Benzyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (1.58 g, 71%). The ester was dissolved in tetrahydrofuran (26 ml), cooled to 0° C. and treated with 2,3-Dichloro-5,6-dicyanobenzoquinone (2.9 g, 12.81 mmol) in tetrahydrofuran (26 ml) and the reaction mixture was reflux for 4 hours. The solvent was removed and the black residue was dissolved in dichloromethane and treated with a 1M aqueous solution of sodium hydroxide. The aqueous solution was extracted several times with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, concentrated and purified by flash chromatography over silica gel (gradient ethyl acetate/methanol: 0-10%) to yield 1-Benzyl-1H-imidazo[4,5-c]pyridin-6-carboxylic acid methyl ester (525 mg, 34%) as a beige solid.
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C=CC=CC=1>C1(C)C=CC=CC=1>[C:9]([O:8][C:7]([NH:6][CH:4]1[CH2:5][C:2](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:3]1)=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 87 %

Procedure:
To a solution of tert-butyl 3-oxocyclobutylcarbamate (1.0 g, 5.4 mmol) in toluene (10 mL) was added ethyl 2-(triphenylphosphoranylidene)acetate (2.1 g, 5.9 mmol). The reaction mixture was heated at 100° C. for 2 hrs, and then concentrated. The residue was purified by silica gel column chromatography (10% EtOAc/petroleum ether) to afford ethyl 2-(3-(tert-butoxycarbonylamino)cyclobutylidene)acetate (1.2 g, 89%). ESI-MS (EI+, m/z): 256 [M+H]+.
Reaction SMILES: C([NH:3][C:4]1[CH:5]=[C:6]([C:14]#[N:15])[C:7]2[N:11]=[CH:10][NH:9][C:8]=2[C:12]=1[CH3:13])=O.Cl.[OH-].[Na+]>O>[NH2:3][C:4]1[CH:5]=[C:6]([C:14]#[N:15])[C:7]2[N:11]=[CH:10][NH:9][C:8]=2[C:12]=1[CH3:13]
Reactant: Cc1c(NC=O)cc(C#N)c2nc[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N)cc(C#N)c2nc[nH]c12
Temperature: 80 °C
Yield: 92 %

Procedure:
A mixture of 6-(Formylamino)-7-methyl-1H-benzimidazole-4-carbonitrile (9) (4.8 kg), water (46 L) and concentrated hydrochloric acid (17.8 kg) is agitated at about 80° C. for about 1½ hours. After the mixture is cooled to about 25° C., a solution of 50% aqueous sodium hydroxide (17.1 kg) and water (64 L) is added. The mixture is cooled to about 25° C. over about 15 minutes. The mixture is then filtered and the product is washed with water (50 L). The product is then dried in a vacuum tray dryer at 45-50° C. and ˜40 torr until dry to obtain 6-Amino-7-methyl-1H-benzimidazole -4-carbonitrile (10) (3.8 kg, 94% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:23]3[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH:32]=3)[C:28]([O:30]C)=[O:29])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].O.Cl>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:23]3[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH:32]=3)[C:28]([OH:30])=[O:29])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(c1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN(c1ccc(F)c(C(=O)O)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.69 h
Yield: 90.9 %

Procedure:
To a solution of methyl 5-[({4-[(4-butylphenyl)ethynyl]phenyl}sulfonyl)(hexyl)amino]-2-fluorobenzoate (207 mg; 0.38 mmol) in anhydrous THF (7 mL) were added lithium hydroxide monohydrate (158 mg; 3.77 mmol) and water (3 mL). The reaction mixture was stirred under MW at 100° C. for 2500 s. Then an aqueous solution of HCl (1N) was added and the mixture extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure to give 185 mg (91.7%) of the title compound as a brown cream. HPLC, Rt: 5.71 min (purity=98.5%). LC/MS, M−(ESI): 534.3. 1H NMR (MeOD) δ: 7.66 (d, J=8.66 Hz, 2H), 7.58 (d, J=8.66 Hz, 3H), 7.46 (d, J=7.91 Hz, 2H), 7.31. (m, 1H), 7.23 (m, 3H), 3.61 (m, 3H), 2.66 (t, J=7.53 Hz, 2H), 1.63 (qt, J=7.34 Hz, 2H), 1.35 (m, 12H), 0.96 (t, J=7.91 Hz, 3H), 0.87 (t, J=6.97 Hz, 3H).