Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([CH2:44][CH2:45][OH:46])[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][N:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([CH2:44][CH2:45][OH:46])[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Reactant: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Temperature: 50 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
A mixture of Intermediate 120c (35 mg, 0.10 mmol), Intermediate 110b (54 mg, 0.15 mmol) and DIPEA (53 μL, 0.30 mmol) in dioxane (1 mL) was stirred at 50° C. overnight. After cooling, the reaction mixture was loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The resultant residue was purified by FCC on silica, using a gradient of 1-8% MeOH in DCM followed by MDAP (Method 7) purification, to afford the title compound (4 mg, 7%) as a glassy white solid. LCMS (Method 5): Rt 3.02 min, m/z 586 [MH+]. NMR (400 MHz, d4-MeOD): 1.20-1.30 (2H, m), 1.25 (9H, s), 1.40-1.52 (1H, m), 1.63-1.83 (3H, m), 1.85-1.92 (2H, m), 2.01 (3H, s), 2.06-2.20 (3H, m), 2.24 (1H, td, J=11.7, 3.1 Hz), 2.31-2.38 (1H, m), 3.04-3.09 (1H, m), 3.76-3.81 (1H, m), 3.81 (2H, t, J=5.4 Hz), 4.08 (2H, t, J=5.4 Hz), 4.98 (1H, dd, J=8.1, 6.5 Hz), 5.36 (1H, t, J=3.8 Hz), 6.12 (1H, s), 7.24 (1H, t, J=7.4 Hz), 7.28-7.37 (3H, m), 7.44 (1H, d, J=7.8 Hz), 7.66 (1H, dd, J=9.9, 0.6 Hz), 8.46 (1H, d, J=1.9 Hz).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C@H:11]12[CH2:17][C@H:14]([NH:15][CH2:16]1)[CH2:13][N:12]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[OH-].[Na+]>O1CCOCC1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:15]1[CH2:16][C@@H:11]2[CH2:17][C@H:14]1[CH2:13][N:12]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: Clc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nc2ccccc2s1

Procedure:
2-Chlorobenzothiazole (2.57 g; 15.1 mmol) tert-butyl(1S,4S)-(−)-2,5-diazabicyclo-[2.2.1]heptane-2-carboxylate (2.0 g; 10.1 mmol) and dioxane (10 ml) was stirred at reflux for 19 days. Aqueous sodium hydroxide (50 ml; 1 M) was added. The mixture was extracted with ethyl acetate (2×50 ml). Chromatography on silica gel with a mixture of ethyl acetate and petroleum (1:3), gave the title compound as free base (oil). Yield 1.7 g (57%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[C:19](OC)=[O:20])=[CH:4][CH:3]=1.[BH4-].[Li+].O.Cl>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH2:19][OH:20])=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)s1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A mixture of 5-(5-chlorothiophen-2-yl)-2-(4-fluorophenyl)-4-methoxycarbonyloxazole (1.8 g) and lithium borohydride (580 mg) in tetrahydrofuran (40 ml) was stirred at room temperature for one hour, and then, refluxed for 1.5 hours. After cooling, water and 10% hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether-ethyl acetate to obtain 5-(5-chlorothiophen-2-yl)-2-(4-fluoro-phenyl)-4-hydroxymethyloxazole (1.48 g) as colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][CH:8]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([OH:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)c1ccc(C)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(O)c1ccc(C)nc1
Reaction time: 6 h

Procedure:
10.0 g (0.048 mol) of 6-methyl nicotinoyl acetic acid ethyl ester (distilled) was dissolved in 200 ml of 95 percent ethanol, mixed with 1 g of 5 percent palladium on activated carbon and poured into a 1-liter autoclave. The autoclave was put under 10 bars of hydrogen and stirred at 20°. The hydrogenation ended after 6 hours. The autoclave was opened, and the reaction solution filtered and evaporated. 10.0 g of 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester remained, which according to NMR and DC was pure. The yield, in relation to the 6-methyl nicotinoyl acetic acid ethyl ester, was 100 percent.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[CH3:12])=[O:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.O>[CH2:13]([NH:20][CH2:2][C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[CH3:12])=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cnn(C)c1NC(=O)CCl
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnn(C)c1NC(=O)CNCc1ccccc1
Temperature: 100 °C

Procedure:
35 g of 5-(chloroacetamido)-1,4-dimethyl-pyrazole are dissolved in 300 ml of absolute dimethyl formamide and the solution, subsequent to the addition of 46 g of benzylamine, heated to 100° C. for 3 h. The cooled solution is diluted with water and extracted with dichloromethane. The dichloromethane phase is washed with a saturated table-salt solution, dried on sodium sulfate, and concentrated by evaporation. The residue is recrystallized from ethyl acetate.
Reaction SMILES: [CH2:1](/[C:4](=[CH:8]\[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])/[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].F[B-](F)(F)F.[H][H]>CO>[C:12]1([S:9]([CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([OH:7])=[O:6])(=[O:11])=[O:10])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC/C(=C\S(=O)(=O)c1ccccc1)C(=O)O
Reactant: [H][H]
Agent: F[B-](F)(F)F
Solvent: CO
Product: CCCC(CS(=O)(=O)c1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 102.5 %

Procedure:
(E)-2-Propyl-3-phenylsulfonylacrylic acid (0.3 g, 1.18 mmol) was dissolved in degassed methanol (15 ml) and [(S,S)-EtDuPHOS Rh (COD)]BF4 (8 mg, 1.18×10−2 mmol) was added under a stream of nitrogen. This solution was injected into the pressure vessel under nitrogen, and then the bomb was charged with hydrogen. The mixture was hydrogenated at 2070 kPa (300 psi) for 3 hour at room temperature. The methanol was removed under reduced pressure to give the title compound (0.31 g, 100% yield). E.e. was determined by chiral HPLC to be 92% e.e. [Chiropak AD; 5% ethanol-95% heptane; 1 ml/min; 254 nm; major enantiomer Rf 18.46 min., minor enantiomer Rf 15.22 min.]
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]3[C:25]=2[CH3:26])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].C(OCC)(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][N:18]2[C:25]([CH3:26])=[C:15]([CH2:14][CH2:13][C:4]3[CH:5]=[CH:6][C:7]4[N:8]=[C:9]([NH:11][CH3:12])[O:10][C:2]=4[CH:3]=3)[N:16]=[C:17]2[CH:22]=1
Reactant: CNC(=O)Nc1ccc(CCc2nc3cc(OC)ccn3c2C)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1nc2ccc(CCc3nc4cc(OC)ccn4c3C)cc2o1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 14.4 %

Procedure:
A mixture of 2-[2-{3-hydroxy-4-(3-methylureido)phenyl}ethyl]-7-methoxy-3-methylimidazo[1,2-a]pyridine (1.9 g) and polyphosphate ester (15 g) was stirred for 1.5 hours at 130° C. To the reaction mixture was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 1 with 6N hydrochloric acid. The separated aqueous layer was adjusted to pH 8 with aqueous potassium carbonate solution. The aqueous mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran with salting-out technique. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was triturated with a mixture of diethyl ether and ethyl acetate, and the resulting precipitate was crystallized from a mixture of methanol, ethyl acetate and isopropyl ether to give 6-[2-(7-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-methylaminobenzoxazole (0.26 g).
Reaction SMILES: [C:1]1(/[CH:7]=[N:8]/[N:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]5)[CH:22]=4)[CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.C([O-])(O)=O.[Na+]>[CH2:7]([NH:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]4)[CH:22]=3)[CH:16]=2)[CH:11]=[CH:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(/N=C/c5ccccc5)c4c3)cn2)CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(NCc5ccccc5)c4c3)cn2)CC1
Yield: 88.6 %

Procedure:
A mixture of tert-butyl 4-[4-(1-{[(E)-phenylmethylidene]amino}-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (200 mg, 0.43 mmol) in MeOH (10 mL) was treated with excess amount of NaBH4 under reflux. HPLC check indicates disappearance of the starting material. The mixture was diluted with aqueous NaHCO3, and extracted with ethylacetate. The product was purified by column chromatography (EtOAc:MeOH=100:5) and the entitled intermediate was isolated as a white solid (180 mg, yield 90%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccccc1
Product: Cc1cc2c(NCCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[N:6]1([CH2:2][CH2:3][CH2:4][OH:5])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1CCNC1
Reactant: OCCCBr
Solvent: Cc1ccccc1
Product: OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Bromopropan-1-ol (27.3 mL, 302 mmol) was added to a solution of pyrrolidine (47.2 g, 655 mmol) in toluene (1000 mL) and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then filtered and the filtrate was evaporated under reduced pressure. The residue was distilled and the title product was obtained as a colourless liquid at 100° C./7 mmHg, (23.1 g, 59%).
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[O:29][CH3:30])=[O:7])[CH2:2][CH2:3][CH3:4].Cl.CN(C)CCCN=C=NCC.[CH3:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([NH2:53])(=[O:52])=[O:51]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([NH:5][C:6]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:53][S:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH3:43])(=[O:52])=[O:51])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Yield: 84.8 %

Procedure:
A solution of 4-[5-(butylcarbamoyl)methyl-1-methylindol-3-ylmethyl]-3-methoxybenzoic acid (0.18 g), 4-(dimethylamino)pyridine (0.06 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.10 g), and 2-methylbenzenesulfonamide (0.08 g) in methylene chloride (3 ml) was stirred under a nitrogen atmosphere for 36 hr. The mixture was diluted with methylene chloride; washed (10% v/v hydrochloric acid, water), evaporated and dried under vacuum to give the title compound (0.21 g, 86%) as a pale pink powder: mp 108°-110°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=O.[C:12](#[N:15])[CH:13]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[CH:13][C:12]#[N:15]
Reactant: Cc1ccc(C(=O)Cl)cc1C
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(C=CC#N)cc1C
Yield: 31.8 %

Procedure:
0.448 g (2 millimols) of palladium acetate, 33.7 g (0.2 mol) of 3,4-dimethylbenzoyl chloride, 13.25 g (0.25 mol) of acrylonitrile and 37.06 g (0.2 mol) of tri-n-butylamine in 200 ml of p-xylene are stirred for 1.5 hours at 120° C. The mixture is then extracted by shaking with 200 ml of 2 N HCl, 200 ml of 2 N NaOH and 100 ml of water, after which it is dried for 15 minutes with 20 g of magnesium sulfate. The crude product is chromatographed on silica gel in methylene chloride, and is recrystallised from n-hexane. 10.0 g (32% of theory) of 3,4-dimethylcinnamonitrile are obtained as pale yellow crystals, melting point 93.9° C. Analysis for C11H11N: calculated C 84.04%, H 7.05%, N 8.91%; found C 83.65%, H 6.87%, N 9.03%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:16])=[C:5]([CH3:15])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[F:17][C:18]([F:26])([F:25])[C:19]([C:20]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]2[C:5]([CH3:15])=[C:4]([CH3:16])[S:3][C:2]2=[N:1][C:21]=1[CH3:22])=[O:24]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Cc1sc(N)c(C(=O)c2ccccc2)c1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc(C)c(C)c2c(-c2ccccc2)c1C(=O)C(F)(F)F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
To a stirred solution of 50 mg (0.22 mmol) (2-Amino-4,5-dimethyl-thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 15) in 2 ml acetic acid was added 0.03 ml (0.22 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 8 mg (11%) 2,2,2-trifluoro-1-(2,3,6-trimethyl-4-phenyl-thieno[2,3-b]pyridine-5-yl)-ethanone as an orange solid. ES-MS m/e (%): 350 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:5]2[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH:8]=[O:9])[CH2:4][CH2:3][CH2:2]1.[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:11]1[CH:12]=[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:6]([OH:13])=[C:7]([CH:10]=1)[CH:8]=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccc(C2CCC2)c1O
Solvent: CC#N
Product: O=Cc1cc(Br)cc(C2CCC2)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-cyclobutyl-2-hydroxybenzaldehyde (2.29 g) was dissolved in acetonitrile (30 mL), and N-bromosuccinimide (5.10 g) was added to the solution at 0° C., and then the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (d).
Reaction SMILES: O.NN.[Br:4][C:5]1[C:6]([O:23][CH3:24])=[C:7]([CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH:8]=[CH:9][CH:10]=1>CCO>[Br:4][C:5]1[C:6]([O:23][CH3:24])=[C:7]([CH2:11][NH2:12])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1c(Br)cccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1c(Br)cccc1CN
Temperature: 90 °C
Yield: 54 %

Procedure:
Hydrazine hydrate (7.8 g, 154 mmol) was added to a suspension of 2-{[3-bromo-2-(methyloxy)phenyl]methyl}-1H-isoindole-1,3(2H)-dione (26.7 g, 77.2 mmol) in EtOH (300 mL) and the reaction mixture was heated to 90° C. for 4 h. After cooling to room temperature, the mixture was filtered and the solid was washed with EtOAc (300 mL×2). The filtrate was evaporated to about 50 mL and filtered again. After removing the solvent, the residue was dissolved in 20 mL of MeOH, and then 1N HCl was added to obtain a white solid. Then the white solid was recrystallized from MeOH-Et2O to obtain 9.0 g of the product (yield: 46.3%). 1H NMR (400 MHz, D2O) δ 3.79 (s, 3H), 4.13 (s, 2H), 7.02 (t, J=7.6 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H); 13C NMR (100 MHz, D2O) δ 37.7, 60.2, 115.6, 125.3, 126.6, 128.8, 133.8, 153.7; MS: m/z 254.1 (M+); HPLC: retention time: 7.618 min; purity: 98.8%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]([NH2:11])[CH2:4][CH2:3]1.Cl.[O:13]([C:15]#[N:16])[K]>O>[O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]([NH:11][C:15]([NH2:16])=[O:13])[CH2:4][CH2:3]1
Reactant: N#CO[K]
Reactant: NC1CCC(=O)c2ccsc21
Agent: Cl
Solvent: O
Product: NC(=O)NC1CCC(=O)c2ccsc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 0.17 g. sample of dl-4,5,6,7-tetrahydro-4-oxobenzo[b]thiophen-7-amine is stirred in 10 ml. of water, acidified with 3N HCl to pH 3-4, and 0.3 g. of KOCN is added. The mixture is stirred at room temperature for 16 hours, and the title compound is collected by filtration, washed with water and dried. It melts at 238°-242° C. and recrystallization from methanol gives analytical sample of the title compound, m.p. 240°-241° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([O:13]C)=[O:12])=[CH:8][C:7]([CH3:15])=[N:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.Cl>>[CH3:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]([CH3:15])=[N:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: COC(=O)c1cc(C)nc2c1c(C)nn2-c1ccccc1
Agent: Cl
Product: Cc1cc(C(=O)O)c2c(C)nn(-c3ccccc3)c2n1
Yield: 81 %

Procedure:
Synthesized using the procedure for 1 except ester 46 was used as the starting material. After the work up and acidifying the aqueous layer with 1N HCl, solid precipitated which was filtered off and dried on high vacuum to provide the title compound (165 mg, 81%) as a light yellow solid. 100% pure by HPLC. 1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H), 8.19 (d, J=7.7 Hz, 2H), 7.56-7.48 (m, 3H), 7.29 (t, J=7.3 Hz, 1H), 2.65 (s, 3H), 2.63 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 167.04, 159.52, 151.67, 142.43, 139.35, 135.32, 129.49, 126.12, 121.13, 118.29, 111.04, 24.92, 16.12. ESI MS: m/z 268.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Reactant: Cc1n[nH]c(N)c1C#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nn2c(-c3ccc(Cl)c(N(C)S(C)(=O)=O)c3)ccnc2c1C#N
Yield: 60.7 %

Procedure:
A mixture of 0.048 g (0.39 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.124 g (0.39 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-methanesulfonamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 89 mg of N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 60.5%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].CO[C:12](OC)(OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:13]1([C:12]2[N:1]3[CH:5]=[CH:4][N:3]=[C:2]3[C:6](=[O:7])[NH:8][N:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNC(=O)c1ncc[nH]1
Reactant: COC(OC)(OC)c1ccccc1
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)n2ccnc12
Reaction time: 0.17 h

Procedure:
A 2.6 gm. portion of 2-imidazolecarboxylic acid hydrazide is added to 200 ml. of ethanol. To this is added 20 ml. of trimethylorthobenzoate. The mixture is refluxed for 31 hours, then the solvents are evaporated giving a white solid which is washed twice with diethyl ether giving 3.0 gm. of white solid. This solid is combined with 50 ml. of diphenyl ether and heated with stirring in an oil bath at 265°-275° C. for 10 minutes. The mixture is cooled, petroleum ether is added and the mixture is filtered. The solid is washed twice with hot petroleum ether, giving 1.4 gm. of the desired product as a light tan solid, m.p. 292°-295° C.
Reaction SMILES: [O:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+]>O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1[O:1][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[CH:4]=1
Reactant: OCCCCc1cc2ccccc2o1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-benzo[b]furanbutanol (2 g), 1,6-dibromohexane (7.7 ml), TAB (500 mg) in 50% w/v sodium hydroxide solution (100 ml) was stirred at room temperature overnight. Water (100 ml) was added and the mixture extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried and concentrated to give an oil. Purification by FCC eluting with hexane:ethyl acetate, 100:0→95:5) gave the title compound as a clear oil (2.1 g) t.l.c. (ether) Rf 0.83.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[N:19]([CH2:34][C@@H:35]5[CH2:40][CH2:39][CH2:38][CH2:37][N:36]5C(OCC5C=CC=CC=5)=O)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=5)[N:22]=4)[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[NH:5][C:4]1=[O:51])[CH3:2].[ClH:52]>>[ClH:52].[ClH:52].[ClH:52].[CH2:1]([CH:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[N:19]([CH2:34][C@@H:35]5[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:32])([F:31])[F:33])[CH:24]=5)[N:22]=4)[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[NH:5][C:4]1=[O:51])[CH3:2]
Reactant: CCC1C(=O)Nc2ncnc(N3CCC(c4nc(-c5ccc(F)c(C(F)(F)F)c5)cn4C[C@@H]4CCCCN4C(=O)OCc4ccccc4)CC3)c21
Agent: Cl
Product: CCC1C(=O)Nc2ncnc(N3CCC(c4nc(-c5ccc(F)c(C(F)(F)F)c5)cn4C[C@@H]4CCCCN4)CC3)c21
Temperature: 50 °C
Yield: 90 %

Procedure:
Charge (2S)-benzyl 2-((2-(1-(5-ethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)piperidine-1-carboxylate (0.45 g; 1.0 eq) in concentrated HCl (10 mL) and heat at 50° C. for 1 hour. After completion, concentrate the reaction mass, strip with toluene and triturate and wash with diethyl ether followed by DCM and pentane. Dry under vacuum to get 0.39 g (90%) of the title compound as an off-white solid. (ES+): m/z=572 (M+H).