Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][C:9]([CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:46]=[CH:45][C:28]([C:29]([NH:31][CH2:32][C:33]([CH3:44])([CH3:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].C(Cl)Cl>>[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].[NH2:35][CH2:34][C:33]([CH3:44])([CH3:43])[CH2:32][NH:31][C:29](=[O:30])[C:28]1[CH:45]=[CH:46][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:47]=[CH:48][C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:7][CH:8]=3)[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)cc3)cc(OCC(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)cc3)cc(OCC(F)(F)F)n2)cc1
Yield: 84 %

Procedure:
tert-butyl (3-(4-((4-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate (35 mg, 0.047 mmol) was stirred in TFA/DCM (1:1) solution (2 mL) for 1 h. The solution was concentrated and free TFA to give N-(3-amino-2,2-dimethylpropyl)-4-((4-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzamide (31 mg, 84%) which was carried to the next step without purification.
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C(O)C.[I-:29].[K+]>O>[I-:29].[CH3:1][CH:2]([N+:14]([CH3:16])([CH3:15])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13]
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N(C)C
Reactant: ClCc1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1=CCCC(C)(C)C1/C=C/C(C)[N+](C)(C)Cc1ccc(Cl)cc1
Yield: 131.7 %

Procedure:
A mixture of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2-(trans)propenyl]dimethylamine (2.2 g), α,4-dichlorotoluene (0.8 g) and ethanol (30 cc) was refluxed for 1 hour, and thereto were added water (100 cc) and potassium iodide (5.0 g). The reaction mixture was extracted with chloroform, and the chloroform layer was dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol to give crystals (3.1 g) of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethyl(4-chlorobenzyl)ammonium iodide.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].C([O-])([O-])=O.[K+].[K+].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[F:12][C:2]([F:1])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: FC(F)(F)Oc1ccccc1S
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2ccccc2OC(F)(F)F)cc1
Temperature: 120 °C
Yield: 73.5 %

Procedure:
To a solution of 2-(trifluoromethoxy)benzenethiol (1.035 g, 5.33 mmol) in DMF (15 mL) at 0° C. was added K2CO3 (921 mg, 6.66 mmol). The solution was warmed to ambient temperature over 10 min before 4-fluorobenzonitrile (613 mg, 5.06 mmol) was added at once. The mixture was heated to 120° C. for 16 hours, then was then cooled and poured onto ice. The mixture was diluted with EtOAc, the layers separated, and the organics were washed successively with sat. NaHCO3 and brine (2×). The organics were dried (MgSO4), filtered, and purified by Biotage SP1 (DCM/hexanes gradient) to afford 4-((2-(trifluoromethoxy)phenyl)thio)benzonitrile (1.098 g, 74%) as a golden oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>[Pd]>[CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc([N+](=O)[O-])c1N1CCCCC1
Agent: [Pd]
Product: Cc1cccc(N)c1N1CCCCC1
Yield: 91 %

Procedure:
Using a procedure similar to Example 3, step (c), 1-(2-methyl-6-nitro-phenyl)-piperidine (74 mg, 0.38 mmol, as prepared in the previous step) was stirred with 5% Pd—C (50 mg) under H2 to afford 66 mg (91%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C12H18N2, 191.1 (M+H), found 191.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:10][N:11]1[CH2:19][CH2:18][CH:14]([C:15](O)=O)[CH2:13][CH2:12]1.[OH-].[Na+]>O>[CH3:10][N:11]1[CH2:19][CH2:18][CH:14]([C:15]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: Nc1cccnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(c2nc3cccnc3[nH]2)CC1

Procedure:
Grams 3.3 of 2,3-diaminopyridine and 5.4 g of N-methylisonipecotic acid hydrocloride are heated at 190° C. for 24 hours. The reaction mixture is cooled and diluted with a small amount of water then made alkaline to pH 10 by addition of NaOH then extracted several times with methylene chloride. The organic extracts are collected together and evaporated to dryness. The residue, crystallized from acetonitrile, gives 2 g (31% of the theoretical value) 2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine melting at 224°-226° C. To a solution constituted by 3 g 2-(1-methylpiperidin-4-yl)-3H-imidazo[4,5-b] pyridine in 10 ml N,N-dimethylformamide 0.6 g 60% sodium hydride are added in portions and subsequently, dropwise, a solution constituted by 1.7 ml p-fluorobenzylchloride in 2 ml N,N-dimethylformamide. The reaction mixture is heated to 100° C. for 2 hours, then cooled and 30 ml water are added thereto. Extraction with diethylether is repeated several times, the ethereal extracts are collected together and evaporated to dryness. The residue product, consisting of 1.1 g 3-(4-fluorobenzyl)-2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine is isolated as fumarate melting at 242°-245° C. (ethyl alcohol).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][O:14][C:41]3[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCS2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCS2
Yield: 76.8 %

Procedure:
0.25 g of (RS)-2-(4,4-dimethyl-thiochroman-6-yl)-heptanol dissolved in 15 ml THF were treated with 250 mg of triphenylphosphine, 150 mg of methyl 4-hydroxybenzoate and 0.15 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 50 ml of ether and washed with two portions of 15 ml of water and one portion of 15 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 280 mg of (RS)-methyl 4-[2-(4,4-dimethyl-thiochroman-6-yl)-heptyloxy]-benzoate as a pale yellow oil. 1H NMR (CDCl3): 7.95 (d, J=8.9 Hz, 2H), 7.21 (d, J=1.9 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.91 (dd, J=8.1, 1.9 Hz, 1H), 6.87 (d, J=8.9 Hz, 2H), 4.10-4.00 (m, 2H), 3.87 (s, 3H), 3.05-2.90 (m, 3H), 2.00-1.80 (m, 3H), 1.70-1.60 (m, 1H), 1.32 (s, 3H), 1.31 (s, 3H), 1.35-1.15 (m, 6H), 0.90-0.80 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].C(N(C(C)C)C(C)C)C.Cl[CH2:23][O:24][CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH2:23][O:24][CH3:25]
Reactant: Oc1cccc2c(F)cccc12
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc2c(F)cccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A solution of 0.257 g of 5-fluoro-1-hydroxynaphthalene in 6 ml of dry dichloromethane was cooled in an ice/salt bath after which was added 0.36 ml (2.07 mmol) of ethyl diisopropylamine followed by 0.15 ml (0.16 g, 1.96 mmol) of chloromethylmethyl ether. The mixture was stirred at 0° C. for 0.5 h after which it was allowed to warm to RT and stirred at RT for 11 h. The mixture was poured into saturated sodium carbonate solution, extracted twice with dichloromethane, dried, filtered and concentrated to an oil. The material was dissolved in a minimum volume of dichloromethane and flash chromatographed on silica gel, eluting with ethyl acetate/heptane to provide 0.260 g (79%) of 5-fluoro-1-methoxymethyloxynaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11]C)=[O:10].[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nnc(Cl)cc1Cl

Procedure:
To a solution of methyl 4,6-dichloro-pyridazine-3-carboxylate (6.01 g, 29.03 mmol, WO 2004/031174) in THF (29 ml) at 0° C. is added 29 ml of aqueous 1.0 M LiOH with stirring. The resulted mixture is stirred continuously at 0° C. for 40 min and monitored by TLC. The reaction mixture is diluted with water, and acidified to pH 1-2 with aqueous 1.0 M HCl. The crude product is suspended between the organic and aqueous layers. After filtration and washed with water and hexane, and dried under vacuum, the product is obtained.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17]([OH:19])=O)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O>O1CCCC1>[C:1]1([C:7]2[C:15]([CH2:16][C:17]([NH2:22])=[O:19])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Solvent: C1CCOC1
Product: NC(=O)Cc1c(-c2ccccc2)nn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A mixture of 3.5 g (0.013 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.24 g (0.013 mole) of 1,1'-carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 3 hours at room temperature while nitrogen was bubbled through the mixture. The reaction mixture was cooled in a dry ice/acetone bath, and treated with 50 ml of liquid ammonia. The reaction mixture was warmed to room temperature and stirred for two days. The suspended solid which formed was collected by filtration (2.81 g, mp 204°-219° C.) combined with the residue from evaporation of the filtrate (3.1 g), and recrystallized from ethanol to give 2.1 g of product (60%), mp 217°-219° C.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[O:6]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Reactant: CC(C)OC(=O)[C@@H]1CCCN1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)[C@@H]1CCCN1C(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
A mixture of 1.50 g (8.10 mmol; 1.0 eq) of 2-fluoro-3-nitrobenzoic acid and 16 ml of thionyl chloride was refluxed for 3 hours. The excess thionyl chloride was then concentrated and the residue was co-evaporated twice with toluene. The resulting acid chloride was taken up in 25 ml of dichloromethane. 1.27 g (8.10 mmol; 1.0 eq) of isopropyl (S)-pyrrolidine-2-carboxylate were added to this mixture cooled to 0° C. The reaction medium was stirred at 0° C. for 30 minutes and then at ambient temperature for 2 hours. The reaction medium was diluted and washed with a 1 M hydrochloric acid solution (100 ml) and then with a saturated sodium hydrogen carbonate solution (100 ml). The organic phase was dried over MgSO4, filtered and evaporated. 2.12 g of isopropyl (S)-1-(2-fluoro-3-nitrobenzoyl)pyrrolidine-2-carboxylate were obtained. Yield=81%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]([C:10]([O:12]CC)=[O:11])=[N:5]1.Cl>[OH-].[Na+]>[F:16][C:2]([F:1])([F:15])[CH2:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]([C:10]([OH:12])=[O:11])=[N:5]1
Reactant: CCOC(=O)C1=NN(CC(F)(F)F)C(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1=NN(CC(F)(F)F)C(=O)C1
Reaction time: 8 h

Procedure:
0.38 Mole (100 g) of 1-(2',2',2'-trifluoroethyl)-3-carbethoxy-2-pyrazolin-5-one were stirred for 1 hour at 90°-95° C. in 900 ml of 1 N sodium hydroxide. The mixture was acidified to pH 1 with concentrated hydrochloric acid and left standing overnight. The precipitate formed was filtered off and rinsed with water
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH2:39][CH3:40]>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]([CH2:39][CH3:40])[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCI
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(=O)n2CC)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 16 h
Yield: 16.8 %

Procedure:
To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11 mg, 0.027 mmol; prepared as in Example 17, Step A) in DMF (2 mL) was added K2CO3 (7.4 mg, 0.053 mmol) and iodoethane (21 mg, 0.13 mmol). The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH 10:1) gave the final product (2 mg). MS (ES+APCI) m/z=441 (M+H). The O-alkylated product was also isolated (See Example 27).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]>C(#N)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[S:13])[S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(Nc1nc2ccc(Cl)cc2s1)n1ccnc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To 6-chlorobenzo[d]thiazol-2-amine (1.14 g, 6.17 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (1.43 g, 8 mmol). The reaction was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (40° C.) for 1 hour to yield N-(6-chlorobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (1.16 g, 3.9 mmol, 64% yield) and then used in the next step without any further purification or characterization.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])([O-])=O.[Na+].[Na+].[CH:28]1(O)[CH2:32]CC[CH2:29]1>>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH:7]1[CH2:32][CH2:28][CH2:29][CH2:8]1)=[O:5])#[N:2]
Reactant: OC1CCCC1
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CC(C(=O)OC1CCCC1)=C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 82 %

Procedure:
83.1 g (0.3 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 100 ml of cyclopentanol and 6 g of Na2CO3 were reacted with one another at 145° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 3 h, the reaction mixture was filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with petroleum ether and dried, giving 78.1 g (82%) of cyclopentyl 2-cyano-3,3-diphenylacrylate as a colorless solid. [λmax 300 nm; E11 (MeOH) 395]
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:32]=[CH:31][C:9]2[N:10]=[C:11]([C:13]3[C:14](=[O:30])[NH:15][CH:16]=[CH:17][C:18]=3[NH:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[OH:22])[NH:12][C:8]=2[CH:7]=1)=O)C.[BH4-].[Na+].[CH3:35]O>C(O)(=O)C>[Cl:29][C:25]1[CH:24]=[C:23]([CH:21]([OH:22])[CH2:20][NH:19][C:18]2[CH:17]=[CH:16][NH:15][C:14](=[O:30])[C:13]=2[C:11]2[NH:12][C:8]3[CH:7]=[C:6]([CH2:4][OH:3])[CH:32]=[C:31]([CH3:35])[C:9]=3[N:10]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CO
Reactant: CCOC(=O)c1ccc2nc(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(CO)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of (±)-2-{4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}- -3H-benzimidazole-5-carboxylic acid ethyl ester (25 mg, 0,054 mmol) in methanol (2 mL) and acetic acid (1 mL) was added NaBH4 (10 mg, 0.27 mmol) at −20° C. The reaction mixture was stirred at −20° C. for 30 min. and quenched with isopropanol (5 drops). After removal of most solvent, the residue was extracted with EtOAc, washed with water and brine, dried over Na2SO4. After concentration, the crude product was purified by prep. HPLC to yield the title compound (18 mg, 62%). 1H NMR (300 MHz, CD3OD) δ 7.50 (1H, s), 7.48 (1H, s), 7.25–7.38 (4H, m), 7.22 (1H, s), 6.25 (1H, d, J=7.6 Hz), 4.89–4.94 (1H, m), 4.76 (2H, s), 3.51–3.62 (2H, m), 2.62 (3H, s). LCMS (M+H)+ m/z 425 (t=1.64 min.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(O[CH:14]=[C:15]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C(N(CC)CC)C>C(#N)C>[C:21]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:2].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]([C:22]([F:23])([F:24])[F:25])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2ccc(OC)cc2)c1C(F)(F)F
Product: O=C(O)C(F)(F)F
Reaction time: 0.03 h

Procedure:
4-Methoxy phenylhydrazine (1 g, 7.24 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (1.408 ml, 7.24 mmol) were stirred in acetonitrile (40 mL) at room temperature. To this mixture was added triethylamine (1.0 mL, 7.24 mmol). LCMS trace of aliquot taken immediately after the addition indicated completion of reaction. The crude mixture was further aged for 1 hr. Volatiles were removed under reduce pressure. The resulting crude mixture was purified by flash chromatography (SiO2, Isolute Flash Si; 100 g). The column was eluted by an EtOAc/hexanes mixture (0% to 20%). Related fractions were pooled and evaporated to afford a yellow oil of 1.4015 g. This oil was further purified by preparative HPLC (reverse phase, Kromasil® 100-5C18, 100×21.1 mm) eluting with acetonitrile/water+0.1% TFA (30% to 100% organic in 10 min, then to 100% for 2 min, 20 mL/min). Related fractions were pooled and evaporated under reduced pressure to afford an oil as a TFA salt of the titled compound.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[C:10](F)=[N:11][CH:12]=[C:13]([I:15])[CH:14]=1>C1COCC1>[Br:8][C:9]1[C:10]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)=[N:11][CH:12]=[C:13]([I:15])[CH:14]=1
Reactant: OCC1CC1
Reactant: Fc1ncc(I)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cc(I)cnc1OCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in mineral oil, 4.32 g) in THF (300 mL) was added cyclopropylmethanol (5.83 g) at 0° C. and the mixture was stirred for 30 min at 0° C. A solution of 3-bromo-2-fluoro-5-iodopyridine (16.3 g) in THF (50 mL) was added to the suspension at 0° C. The suspension was allowed to warm to r.t. and stirred for 18 h. The suspension was poured into ice water and then extracted with EA (200 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by SGC (eluent: PE) to give the subtitle compound. MS ESI+: m/z=354 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[SH:12][CH2:13][CH2:14][C:15]([N:17]([CH3:29])[C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)=[O:16].C(OCC)(=O)C>ClCCCl>[C:8](=[O:10])([S:12][CH2:13][CH2:14][C:15]([N:17]([CH3:29])[C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)=[O:16])[CH3:9]
Reactant: CC(=O)Cl
Reactant: CN(C(=O)CCS)c1nnc(-c2cccnc2)s1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(=O)N(C)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
Triethylamine (12 μL, 0.086 mmol, 1.2 equiv) and acetyl chloride (6 μL, 0.08 mmol, 1 equiv) were sequentially added to a stirred solution of 3-mercapto-N-methyl-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (20 mg, 0.071 mmol, 1.0 equiv) in 1,2-dichloroethane (1.4 mL) at 23° C. The resulting pale yellow solution was stirred at 23° C. for 16 h. The reaction mixture was directly subjected to silica gel column chromatography (ethyl acetate) to afford the title compound as a white powder (23 mg, 99%): mp 133-135° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (d, J=2 Hz, 1H), 8.69 (dd, J=5, 2 Hz, 1H), 8.27 (dt, J=8, 2 Hz, 1H), 7.42 (dd, J=8, 5 Hz, 1H), 3.82 (s, 3H), 3.26 (t, J=7 Hz, 2H), 3.03 (t, J=7 Hz, 2H), 2.36 (s, 3H); ESIMS m/z 323 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]#[N:11].[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:11][C:10]1[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=2[S:14][C:13]=1[C:12]([O:16][CH3:17])=[O:15]
Reactant: N#Cc1cccc(C#N)c1Cl
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2c(C#N)cccc2c1N
Yield: 65 %

Procedure:
2-chloro-1,3-dicyanobenzene (972 mg, 6.0 mmol) was treated with 1 eq of methyl thioglycolate and 1 eq sodium carbonate in methanol as described in Example 41A to give the title compound in 65% yield. 1H NMR (300 MHz, D6-DMSO d 3.83 (s, 3H), 7.38 (bs, 2H), 7.62 (t, J=8 Hz, 1H), 8.10 (d, J=8 Hz, 1H), 8.50 (d, J=8 Hz, 1H). MS (DCI/NH3) m/e 250 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([OH:18])=O)=[O:5])[CH3:2].[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CCNCC
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)N(CC)CC

Procedure:
Starting materials: 11-ethoxycarbonyl-2,6,10-trimethyl-2,6,10-undecatrienoic acid and diethylamine.