Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[C:2]1([CH3:27])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[S:20][C:21]([C:24]([O-])=[O:25])=[CH:22][N:23]=3)[CH:14]=2)[O:9]1.CN(C)C=O.ON1C2C=CC=CC=2N=N1.C[N:44]1CC[O:47][CH2:46][CH2:45]1.C(CN)O>O>[OH:47][CH2:46][CH2:45][NH:44][C:24]([C:21]1[S:20][C:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[O:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:27])[CH2:17][CH2:16]3)=[N:23][CH:22]=1)=[O:25]
Reactant: Cc1ccccc1C1CCc2cc(Oc3ncc(C(=O)[O-])s3)ccc2O1
Reactant: CN1CCOCC1
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: NCCO
Product: Cc1ccccc1C1CCc2cc(Oc3ncc(C(=O)NCCO)s3)ccc2O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid lithium salt (100 mg, 0.27 mmol) in dimethylformamide (2 ml) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol, 1.4 eq), 1-hydroxy-benzotriazole (51 mg, 0.38 mmol, 1.4 eq) and N-methylmorpholine (68 mg, 0.67 mmol, 2.5 eq) were added and the mixture was stirred at room temperature for 15 min. Ethanolamine (25 mg, 0.40 mmol, 1.5 eq) was added and stirring was continued for 16 h. The mixture was diluted with water and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with a diluted aqueous solution of sodium carbonate and brine, dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol gradient). The desired compound was obtained as a white powder (43 mg, 39%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.CC(C)([O-])C.[K+].C1COCC1.C[O:27][C:28](=O)[C:29]([C:31]1[C:39]2[C:34](=[CH:35][C:36]([Br:40])=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=O>CN(C=O)C>[Br:40][C:36]1[CH:35]=[C:34]2[C:39]([C:31]([C:29]3[C:28](=[O:27])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:32][NH:33]2)=[CH:38][CH:37]=1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2cc(Br)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cc(Br)ccc45)C(=O)NC3=O)c21
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
To solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.300 g, 1.59 mmol) in DMF (15 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.59 mL, 1.59 mmol), followed after 5 minutes by (6-bromo-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.235 g, 0.83 mmol) in DMF (1.25 mL). After another 5 minutes additional potassium tert-butoxide (1.59 mL) was introduced followed by the additional (6-bromo-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.235 g, 0.83 mmol) in DMF (1.25 mL). The reaction was stirred for 5 minutes and an additional potassium tert-butoxide (1.59 mL) was introduced. After heating at 50° C. over night, then deep red solution and was cooled to room temperature, quenched with 1N HCl and poured in EtOAc. The two layers were separated and the organic layer was washed with H2O, saturated aq NaHCO3, and brine (×3), dried (MgSO4), filtered, and concentrated. Flash chromatography (80% EtOAc/hexane) gave the title compound (0.256 g, 38%) as a red solid. 1H NMR (400 MHz, DMSO-d6) 3.64 (s, 3H), 6.26 (d, J=4.4 Hz, 1H), 6.47 (d, J=2.8 Hz, 1H), 6.60 (dd, J=2, 8.8 Hz, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.98 (dd, J=7.2, 7.2 Hz, 1H), 7.24 (d, J=3.6 Hz, 1H), 7.61 (dd, J=1.2, 8 Hz, 1H), 7.87 (d, J=2.8 Hz, 1H), 11.18 (s, 1H), 11.91 (s, 1H). MS (electrospray, m/z) 420/418 (M−−1).
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[N:7]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH:5]=1)=[N+]=[N-].O>C(OCC)(=O)C.C(O)C>[F:23][C:19]1[CH:18]=[C:17]([C:6]2[CH:5]=[C:4]([NH2:1])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=3)[N:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=Nc1cc(-c2cccc(F)c2)nc2ccc([N+](=O)[O-])cc12
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1ccc2nc(-c3cccc(F)c3)cc(N)c2c1
Yield: 88 %

Procedure:
Into a 500 mL three-neck flask equipped with a condenser, magnetic stirrer, nitrogen inlet gas outlet and a silicone oil heating bath was placed 4-azido-2-(3-fluorophenyl)-6-nitro-quinoline. The material was suspended in 250 mL of ethyl acetate and 50 mL of ethanol. The stirred mixture was heated to reflux, then 20 g (89 mmoles, 6 equiv.) of stannous chloride dihydrate was cautiously added portionwise over 40 min. The reaction was then heated for an additional 2 hr. At the end of this time, the reaction was cooled and then poured into 500 mL of water. The pH was cautiously adjusted to 9.0 and the solution filtered. The solids were washed with 100 mL of ethyl acetate, the filtrates combined and the aqueous layer extracted twice with 200 mL of ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The product was chromatographed on a silica gel column, using 10% methanol in ethyl acetate as eluent, and was then recrystallised from methylene chloride and hexane to give 3.6 g (88%) of the product.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](OCC)(=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].CC([O-])(C)C.[K+].Cl.[NH2:24][NH2:25]>CCO.C1COCC1.O>[CH2:11]([O:10][C:8]([C:7]1[C:2]2[CH2:3][CH2:4][CH2:5][C:1]=2[NH:25][N:24]=1)=[O:9])[CH3:12]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NN
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1n[nH]c2c1CCC2
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
To a solution of cyclopentanone (42.0 g, 0.50 mol) and diethyl oxalate (73.1 g, 0.50 mol) in EtOH (2.5 L) at rt under N2 was added a solution of KOt-Bu in THF (500 mL of a 1M solution, 0.50 mol) over 0.5 h via an addition funnel. The reaction was stirred for 3.5 h at which time the flask was cooled to 0° C. Hydrazine hydrochloride (37.6 g, 0.55 mol) in H2O (250 mL) was added via addition funnel over 0.5 h. The reaction was warmed to rt and stirred for 16 h. The volatiles were removed in vacuo and the resulting solid was washed with NaHCO3 (sat. aq., 500 mL) and H2O (500 mL). Further concentration in vacuo gave pure 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester (63.6 g, 0.35 mol, 71% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:21][C:22]1[C:26](Br)=[CH:25][S:24][CH:23]=1.[F-].[K+]>CN1CCCC1=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:21][C:22]1[C:26]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:25][S:24][CH:23]=1
Reactant: Brc1cscc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Fc1ncccc1-c1cscc1Br
Temperature: 100 °C
Yield: 27.6 %

Procedure:
A mixture of 2-fluoro-3-tributylstannylpyridine (1.9 g), 3, 4-dibromothiophene (1.5 g) and Pd(Ph3P)2Cl2 (0.175 g) in N-methylpyrrolidinone (7.5 mL), in a sealed tube, was heated at 100° C. for 16 hours. The mixture was cooled and stirred with aqueous potassium fluoride for 6 hours. The mixture was diluted with ethyl acetate, washed with water, dried filtered and evaporated. The residue was fractionated by chromatography to give 3-bromo-4-(2-fluoropyridin-3-yl)thiophene (0.35 g), mp 48-50° C.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.[O:32]=[C:33]1[NH:37][C:36]([C:38]#[N:39])=[CH:35][N:34]1[CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[O:46]1CCC[CH2:47]1>>[C:38]([C:36]1[NH:37][C:33](=[O:32])[N:34]([CH:40]2[CH2:45][CH2:44][N:43]([C:47]([NH:1][C@@H:2]3[N:8]=[C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:6]4[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=4[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]3=[O:24])=[O:46])[CH2:42][CH2:41]2)[CH:35]=1)#[N:39]
Reactant: N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: N#Cc1cn(C2CCNCC2)c(=O)[nH]1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cn(C2CCN(C(=O)N[C@@H]3N=C(c4ccccc4)c4ccccc4N(CC(F)(F)F)C3=O)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R)-3-Amino-5-phenyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (38 mg, 0.114 mmol) (Y.-J. Shi et al., Tetrahedron, 1999, 55, 909-918) and triethylamine (0.017 mL, 0.120 mmol) were added to a solution of p-nitrophenylchloroformate (23 mg, 0.114 mmol) in tetrahydrofuran (15 mL) at 0 oC. After 1 h, 2-oxo-1-piperidin-4-yl-2,3-dihydro-1H-imidazole-4-carbonitrile (23 mg, 0.120 mmol) and additional triethylamine (0.034 μL, 0.240 mmol) were added. The reaction warmed to ambient temperature and was then heated to 50 oC. After 2 h, the reaction was concentrated and then partitioned between dichloromethane and saturated sodium bicarbonate. The organics were washed with water, brine, and dried over magnesium sulfate. Purification by silica gel chromatography (100% dichloromethane→7% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (40 mg). MS 552.195 (M+1)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([OH:21])=[O:20])[CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)c1
Yield: 74.8 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and m-aminobenzoic acid (0.714 g, 0.0052 mol) were refluxed as above overnight. Crystallisation of the product from MeOH yielded 1.21 g (72%) of 106 as a white solid: mp=>380° C.; Rf0.87 (A): Rf0.75 (C): Rf0.27 (D):IR (cm−1): 2700-3125 (OH), 3090 (C═CH), 2665 (C—H), 1780 (C═O), 1731 (C═O), 1699 (C═O), 1610 (C═C), 1589 (C═C), 1484 (C═C), 1452 (C═C), 1383 (C—O), 1310 (C—O), 1222 (C—O), 722 (C═CH); MS m/z (rel intensity) 311 (22), 310 (100).
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[C:4]2[CH:3]=[CH:2][O:1][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]ccc2occc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2occc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Furo[3,2-c]pyridin-4(5H)-one (72.2 g, 534 mmol) was added to phosphorus oxychloride (100 mL) heated to 120° C., and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure. Ice-cooled water was added to the residue, and the mixture was basified with 8M aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70) to give the title compound (66.1 g, yield 81%).
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CCOCC>[CH3:17][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH:12]([NH:14][C:25](=[O:26])[O:27][CH2:28][CH3:29])[CH3:13])=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)=CCOc1ccc(OCC(C)N)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)NC(C)COc1ccc(OCC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the above amine (0.86 g, 3.7 mmol) and pyridine (0.64 g, 8.0 mmol) in 8 ml of ether at 5° is added dropwise over 10 min. ethyl chloroformate (0.43 g, 4.0 mmol) in 2 ml of ether. The mixture is stirred at 5° for 1 hour and is then allowed to warm to RT. Excess ethyl chloroformate is quenched with water and the reaction mixture is poured into water and ether and the aqueous phase is extracted with ether (3×). The combined organic layers are washed with 2N ammonium sulfate, with 10% sodium carbonate, then with water until neutral and with brine. The organic layer is dried, filtered, the solvent removed and the product purified by prep. TLC to give ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]-1-methylethyl}carbamate m/s (M+) 307.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([O:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][CH:3]=1)[CH:29]=[CH2:28]
Reactant: COc1ccc(Cc2oc3c(Cl)ccc(O)c3c2C)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c12
Temperature: 25 °C
Yield: 113.2 %

Procedure:
To a solution of 4-hydroxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran (164) (Example 44) (1.5 g, 5 mmol) in 30 mL acetone was added potassium carbonate (690 mg, 5 mmol) and allyl bromide (605 mg, 5 mmol). The mixture was refluxed for 20 h, then filtered through celite after cooling to room temperature. Concentration of the filtrate gave 1.94 g of the 4-allyloxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran as a light brown oil. The crude material was refluxed in 8 mL o-dichlorobenzene for 6 h. Evaporation of the solvent followed by chromatography gave the title compound as a white solid, mp 90°-93° C
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:19])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[C:8]([CH:16]([CH3:18])[CH3:17])=[CH:7]2)[CH:2]=[CH2:3].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][CH2:3][C:2]1[O:19][C:5]2=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]2[CH:1]=1)[NH:10][C:9](=[O:15])[C:8]([CH:16]([CH3:17])[CH3:18])=[CH:7]3
Reactant: C=CCc1cc(C)c2[nH]c(=O)c(C(C)C)cc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1cc2cc(CBr)oc2c2cc(C(C)C)c(=O)[nH]c12
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 109.3 %

Procedure:
6-Allyl-5-hydroxy-3-isopropyl-8-methylcarbostyril (1.50 g, 5.34 mmol) was dissolved in chloroform (100 ml). N-bromosuccinimide (1.10 g, 6.18 mmol) was added to the solution, and the mixture was stirred at 75° C. for 90 minutes. The reaction mixture was extracted from chloroform-water, and the organic phase was washed with saturated aqueous NaCl solution, dried, and condensed under reduced pressure. The residue was recrystallized from chloroform -ethyl acetate-ether to obtain 1.95 g of the title compound as pale yellow needles (99.4%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F-:11].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N.O.CCOC(C)=O>[F:11][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: [F-]
Reactant: O=C(CBr)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C(CF)c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of 2-bromoacetophenone (Aldrich Chemical Company) (5.42 g, 27.3 mmol), KF (6.32 g, 0.11 mol) and 18-crown-6 (3.61 g, 13.7 mmol) in CH3CN (150 mL) was heated at 90° C. for 16 h under a N2 atmosphere. Heating was discontinued and the mixture was allowed to cool to room temperature. The mixture was diluted with H2O (300 mL) and EtOAc (400 mL) and transferred to a separatory funnel. The organic solution was separated, washed with H2O (2×300 mL), saturated NaCl (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The resulting crude ketone (3.02 g) was used without further purification (see Gregory et al. J. Med. Chem. 1990, 33 (9), 2569).
Reaction SMILES: S1C=CC=C1.[F:6][C:7]1[CH:18]=[CH:17][C:10]2[S:11][CH:12]=[C:13]([CH2:14][C:15]#[N:16])[C:9]=2[CH:8]=1.CO>N.C(Cl)(Cl)Cl.[Ni]>[F:6][C:7]1[CH:18]=[CH:17][C:10]2[S:11][CH:12]=[C:13]([CH2:14][CH2:15][NH2:16])[C:9]=2[CH:8]=1
Reactant: N#CCc1csc2ccc(F)cc12
Agent: [Ni]
Agent: N
Solvent: c1ccsc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCCc1csc2ccc(F)cc12
Temperature: 10 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Methanolic ammonia solution (15 mL) and thiophene solution (1 mL) were added to Raney Ni (5 g) taken in a reaction flask. This was followed by the addition of (5-Fluoro-benzo[b]thiophen-3-yl)-acetonitrile (I-45b: 700 mg, 3.66 mmol) in methanolic ammonia solution (15 mL) at 0° C. The resulting reaction mass was stirred at 10° C. overnight under hydrogen atmosphere. The reaction was monitored by TLC (5% methanol in chloroform). The reaction mass was filtered, washed with methanol and the filtrate was concentrated under reduced pressure to afford 500 mg of the crude product which was used for the next step without further purification. LCMS: 92.76%, m/z=196.1 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:18][C:11]3[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.[Cl:57][C:58]1[CH:73]=[CH:72][C:61]([O:62][CH2:63][C:64]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[O:65])=[CH:60][CH:59]=1>CC#N>[Cl:57][C:58]1[CH:59]=[CH:60][C:61]([O:62][CH2:63][C:64]([N:66]2[CH2:71][CH2:70][N:69]([C:15]3[C:10]4[CH:9]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[S:18][C:11]=4[N:12]=[C:13]([CH3:17])[N:14]=3)[CH2:68][CH2:67]2)=[O:65])=[CH:72][CH:73]=1
Reactant: Cc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a solution of 6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (40 mg, 0.15 mmol) and BOP (88 mg, 0.20 mmol) in CH3CN (1 ml) was added DBU (34 μl, 0.23 mmol). After stirring for 10 minutes at room temperature, 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (59 mg, 0.23 mmol) was added. The reaction was stirred at room temperature overnight and then heated at 60° C. for 4 hours. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (66 mg, 86%).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:10]=1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.O>CN(C)C=O>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]([CH2:25][C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=2)[N:10]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: CC(C)CCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of N-(3-methylbutyl)-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (500 mg, 1.59 mmol) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride (63.6 mg, 1.59 mmol) and the mixture was stirred for 30 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (462 mg, 1.45 mmol) was added and the obtained mixture was stirred at room temperature for 13 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (490 mg, yield 57%) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:19]=[N:20][C:21]([O:28][CH2:29][CH2:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[N:14]=[C:13]([C:37]#[N:38])[C:12]=2[N:11]=[N:10]1.C(N(CC)C(C)C)(C)C.[Cl:48][CH2:49][C:50]([N:52]([CH3:54])[CH3:53])=[O:51]>C(#N)C>[ClH:48].[CH3:8][N:9]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:19]=[N:20][C:21]([O:28][CH2:29][CH2:30][CH:31]4[CH2:36][CH2:35][N:34]([CH2:49][C:50]([N:52]([CH3:54])[CH3:53])=[O:51])[CH2:33][CH2:32]4)=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=3)[N:14]=[C:13]([C:37]#[N:38])[C:12]=2[N:11]=[N:10]1
Reactant: Cn1nnc2c(C#N)nc(-c3cnc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Reactant: CN(C)C(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)CN1CCC(CCOc2ncc(-c3cc4c(nnn4C)c(C#N)n3)cc2C(F)(F)F)CC1
Product: Cl
Temperature: 20 °C
Reaction time: 65 h
Yield: 88.3 %

Procedure:
To a solution of 1-methyl-6-(6-(2-(piperidin-4-yl)ethoxy)-5-(trifluoromethyl)-pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile trifluoroacetate (200 mg) and N,N-diisopropylethylamine (310 μl) in acetonitrile (8 ml), 2-chloro-N,N-dimethylacetamide (77 μl, 91 mg) was added and the mixture stirred at 20° C. for 65 h. The reaction mixture was concentrated. The residue diluted with water (20 ml) and extrated with DCM (50 ml×3), combined DCM layer dried over sodium sulphate and solvent removed under reduced pressure. The residue was then purified by Strata Si column (5 g, dichloromethane:methanol=1:0, 25:1 to 15:1), converted to hydrochloric acid salt using 2N hydrochloric acid in diethyl ether to give 1-methyl-6-(6-(2-(1-(2-dimethylamino-2-oxo-ethyl)piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile hydrochloride (179 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.CC[N:16](CC)CC.N>C1COCC1>[NH2:16][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([Cl:1])[N:3]=[C:4]([S:12][CH3:13])[N:5]=1
Reactant: CCN(CC)CC
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: N
Solvent: C1CCOC1
Product: CSc1nc(N)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine (327 mg, 1.36 mmol) in THF (5.4 mL) at −10° C. was added Et3N (474 μL, 3.40 mmol) followed by a solution of NH3 (2.0 M in MeOH, 750 μL, 1.5 mmol). The mixture was stirred while warming to 0° C. for 1.5 h (LC/MS indicated consumption of starting materials). The reaction mixture was taken forward without work-up.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[CH:18](OCC)(OCC)OCC.N([O-])=O.[Na+]>C(O)(=O)C.CN(C)C=O.O>[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]([N:17]2[CH:18]=[N:3][N:2]=[N:1]2)=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-n2cnnn2)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium azide (0.54 g) was added to a stirred solution of 2-methoxy-5-amino benzoic acid, methyl ester (1 g ) and triethyl orthoformate (1.38 ml) in glacial acetic acid (8 ml) and dimethylformamide (2 ml). The mixture was heated to 79°-80°. After 11/4 h the solution was allowed to cool (ice-water bath) and a solution of sodium nitrite (0.57 g) in water (10 ml) was added slowly. After stirring for 30 min, water (40 ml) was added. After 2 h, the mixture was filtered. The residual white solid was washed with water and dried in vacuo, at 25° to give the title compound (0.83 g); mp 185°-187°.