Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)[CH:34]=[C:35]([F:38])[C:36]=1[F:37].O>C1COCC1>[F:30][C:31]1[CH:32]=[C:33]([CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][C:44](=[CH:2][O:3][CH3:4])[CH2:43][CH2:42]2)[CH:34]=[C:35]([F:38])[C:36]=1[F:37]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(CCc2cc(F)c(F)c(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC=C1CCC(CCc2cc(F)c(F)c(F)c2)CC1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
A suspension of methoxymethyltriphenylphosphonium chloride (112.3 g) in THF (300 ml) was stirred in a nitrogen gas stream, followed by adding potassium-t-butoxide (45.4 g) little by little while cooling at 0° C., stirring the reaction solution at room temperature for one hour, dropwise adding 4-(2'-(3",4",5"-trifluorophenyl)ethyl)cyclohexanone (70 g)in THF (200 ml), raising the temperature of the reaction mixture up to room temperature, further stirring for 2 hours, adding to water (500 ml) after completion of the reaction, extracting with ethyl acetate (500 ml), drying the organic layer over anhydrous MgSO4, concentrating under reduced pressure, and carrying out chromatography treatment on silica gel with ethyl acetate/heptane (1:5), to obtain 4-(2'-(3",4",5"-trifluorophenyl)ethyl)methoxymethylenecyclohexane (53.7 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].[CH3:37][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:37])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: C[Zn+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.371 mmol) and tetrakis(triphenylphosphine)palladium (8.6 mg, 7.4 μmol) in THF (5 mL) was added a 2 M solution of methylzinc chloride in THF (0.371 mL, 0.742 mmol). The suspension was stirred for 16 h at 60° C. The reaction mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified via column chromatography, eluting with 0-100% EtOAc/DCM. The desired fractions were combined and concentrated to generate 90 mg (0.174 mmol, 46.8% yield) of the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.47 (d, J=5.3 Hz, 1H), 7.52-7.58 (m, 1H), 7.40-7.50 (m, 4H), 7.29 (t, J=7.8 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 2.58 (s, 3H), 1.42 (s, 9H). MS (ESI): 520.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[C:6]([O:18]C)[CH:7]=[CH:8][C:9]=2[C:11](F)(F)[C:12]([NH:14]F)=O)[NH:4][N:3]=1.[BrH:20]>>[BrH:20].[OH:1][C:2]1[C:10]2[C:5](=[C:6]([OH:18])[CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][NH2:14])[NH:4][N:3]=1
Reactant: COc1ccc(C(F)(F)C(=O)NF)c2c(O)n[nH]c12
Agent: Br
Product: NCCc1ccc(O)c2[nH]nc(O)c12

Procedure:
Under argon, 750 mg of N-[2-(3-hydroxy-7-methoxy-1H-indazol-4-yl]trifluoroacetamide is heated to 120° C. with 5 ml of aqueous hydrogen bromide (65%) for 2 hours. The crystallized product is recrystallized from methanol/diethyl ether, yielding 680 mg of 2-(3,7-dihydroxy-1H-indazol-4-yl)ethylamine, hydrobromide, decomposition point 270°-273° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10](C(=O)C)[N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(B(O)O)=CC=1.[Br:26]C1N=C(Cl)SN=1>>[Br:26][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[S:12][N:11]=1
Reactant: CC(=O)c1nsc(-c2ccc(F)cc2)n1
Reactant: Clc1nc(Br)ns1
Agent: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2nc(Br)ns2)cc1

Procedure:
In another embodiment, 1-(5-(4-fluorophenyl)-1,2,4-thiadiazol-3-yl)ethanone is prepared according to the methodology and reagents of Scheme 17A. Specifically, 4-fluorophenyl boronic acid is reacted with 3-bromo-5-chloro-1,2,4-thiadiazole to provide 3-bromo-5-(4-fluorophenyl)-1,2,4-thiadiazole. 3-Bromo-5-(4-fluorophenyl)-1,2,4-thiadiazole is then reacted with a tin reagent such as tributyl(1-ethoxyvinyl)-stannane to convert the bromide moiety of 3-bromo-5-(4-fluorophenyl)-1,2,4-thiadiazole to an acetyl group. In one embodiment, this reaction is performed in the presence of a catalyst such as PdCl2(PPh3)4. In another embodiment, the reaction is performed in DMF at elevated temperatures overnight. 1-(5-(4-Fluorophenyl)-1,2,4-thiadiazol-3-yl)-ethanone may then converted to a compound of Formula (I-A) by the methods described herein, such as Scheme 1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:20]C(=O)OC(C)(C)C)[S:9][C:10]=1[C:11]([C:13]1([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]>FC(F)(F)C(O)=O>[CH3:19][C:13]1([C:11]([C:10]2[S:9][C:8]([NH2:20])=[N:7][C:6]=2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:12])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)C2(C)CCOCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C(=O)c2sc(N)nc2-c2ccco2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Compound 582 (210 mg, 0.535 mmol) was dissolved in trifluoroacetic acid (2 mL), followed by stirring at room temperature for 1 hour. The solvent was distilled away under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 583 (156 mg, 100%).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([O:27][CH3:28])[C:15]=1[C:16](O)=[O:17]>>[CH3:28][O:27][C:19]1[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=[C:14]([O:13][CH3:12])[C:15]=1[C:16]([NH:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: COc1cc(C(F)(F)F)cc(OC)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: COc1cc(C(F)(F)F)cc(OC)c1C(=O)NC1CCCC1N1CCCC1

Procedure:
The title compound, yellow oil, MS: m/e=387.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,6-dimethoxy-4-trifluoromethyl-benzoic acid (intermediate AJ).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20].C1C(=O)N([Cl:30])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])=[CH:4][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Cl:30]
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(c2cc(Cl)c(N)c(OCC(F)(F)F)c2)CCC1
Temperature: 25 °C
Yield: 18.1 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.0 g, 6.3 mmol) in dry CHCl3 (30 mL), NCS (0.842 g, 6.3 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.4 g) as thick syrup.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Br.[Cl-].[Li+].[CH2:17]([Sn](CC)(CC)CC)[CH3:18]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:17][CH3:18]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: CC[Sn](CC)(CC)CC
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1ccc([N+](=O)[O-])cc1C(=O)OC
Temperature: 100 °C
Yield: 55.9 %

Procedure:
2-Bromo-5-nitrobenzoic acid methyl ester (1.0 g), lithium chloride (0.49 g), tetraethyltin (0.96 g) and bis(triphenylphosphine)-palladium(II)chloride (0.1 g) were combined in dimethylformamide (20 ml) and heated at 100° C. for 8 h. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane/petroleum ether 30:70) to give the title compound (0.45 g). 1H NMR (CDCl3) δ: 1.28 (3H, t, J=7.4 Hz), 3.10 (2H, q, J=7.4Hz), 3.96 (3H, s), 7.47 (1H, d, J=8.5 Hz), 8.27 (1H, dd, J=2.5, 8.5 Hz), 8.73 (1H, d, J=2.5 Hz)
Reaction SMILES: [H-].[Na+].F[C:4]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].CS(CCO)(=O)=[O:15]>CN(C=O)C>[F:12][C:11]1[C:4]([OH:15])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: CS(=O)(=O)CCO
Reactant: N#Cc1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(F)c1O
Temperature: 25 °C

Procedure:
Sodium hydride was added to a DMF solution of 2,3-difluorobenzonitrile and 2-(methylsulfonyl)ethanol, followed by stirring at room temperature to obtain 3-fluoro-2-hydroxybenzonitrile. FN: 136.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[CH:13]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)=O.[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=1[NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1.O>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=1[NH:24][CH2:1][C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[CH:13]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1
Reactant: CSc1ncc(C=O)c(Nc2cccc(CCO)c2)n1
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2cccc(CCO)c2)n1
Yield: 16.6 %

Procedure:
A solution of 4 g (13.8 mmol) of 5-formyl-4-[3-(2-hydroxyethyl)phenyl]amino-2-methylthiopyrimidine in 80 ml of toluene was treated with 2.4 g (15 mmol) of 2,6-dichloroaniline and 0.25 g (1.3 mmol) of 4-toluenesulfonic acid monohydrate and the mixture was heated under reflux with azeotropic removal of water for 18 hours and then cooled. The mixture was evaporated and the residue was dissolved in 40 ml of tetrahydrofuran and added dropwise to a solution of 0.6 g (16 mmol) of lithium aluminium hydride in 40 ml of tetrahydrofuran. After 1 hour the reaction was quenched by the cautious dropwise addition of 0.6 ml of water, 0.6 ml of 2M aqueous sodium hydroxide and 1.8 ml of water. The resulting suspension was filtered through a filter aid and the filtrate was evaporated. The residue was subjected to column chromatography on silica using dichloromethane/methanol for the elution in a gradient from a ratio of 50:1 to a ratio of 10:1. Product-containing fractions from the first product to be eluted from the column were combined and evaporated to give 1 g (17%) of 5-(2,6-dichloroanilino)methyl-4-[3-(2-hydroxyethyl)phenyl]amino-2-methylthiopyrimidine as a white solid. Mass spectrum (ESI) MH+ =435. Product-containing fractions from the second product to be eluted from the column were combined and evaporated to give 1.8 g (45%) of 5-hydroxymethyl-4-[3-(2-hydroxyethyl)phenyl]amino-2-methylthiopyrimidine as a white solid. [Mass spectrum (ESI) MH+ =292].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].N1CCCCC1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:14]([C:13](=[O:18])[CH3:12])[C:15](=[O:17])[CH3:16])[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1cc(F)c(F)c(F)c1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cc(F)c(F)c(F)c1)C(C)=O

Procedure:
A stirring mixture of 3,4,5-trifluorobenzaldehyde (4.2 g, 26.2 mmol), 2,4-pentanedione (2.62 g, 26.2 mmol), piperidine (0.430 g, 5 mmol) in benzene (150 mL) was heated at reflux temperature (equipped with a Dean-Stark trap) for 8 h. The benzene was evaporated, the yellow oily residue, 2-{(3,4,5-trifluorophenyl)-methylene}-2,4-pentanedione, was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36]([Cl:40])=[C:37]([NH2:39])[CH:38]=1)(=[O:33])=[O:32]>>[Cl:40][C:36]1[S:35][C:34]([S:31](=[O:33])(=[O:32])[NH:30][CH2:29][CH2:28][OH:27])=[CH:38][C:37]=1[NH:39][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cc(S(=O)(=O)NCCO)sc1Cl
Product: O=C(Nc1cc(S(=O)(=O)NCCO)sc1Cl)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (example B.6) according to general procedure II. Yellow solid. MS (ISP) 612.0 [(M−H)−]; mp 191° C.
Reaction SMILES: S([Cl:5])(O)(=O)=O.O.[N:7]([CH2:14][CH2:15][OH:16])([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10]>>[ClH:5].[N:7]([CH2:14][CH2:15][OH:16])([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10]
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: OCCN(CCO)CCO
Product: Cl
Reaction time: 1 h

Procedure:
A suspension of 3.7 g of the sulfochloride of the formula (7) in 15 g of triethanolamine and 3 g of water is stirred at 150° for one hour. The excess solvent is substantially removed in vacuo at 120°-150° C., and 50 ml of isopropanol are added to the viscous residue. The precipitated product is filtered off with suction, washed repeatedly with isopropanol and taken up in approx. 40 ml of water. The cloudy solution is clarified by filtration with 0.2 g of active charcoal through a pressure filter. This gives an aqueous solution of the bistriethanolamine salt of the formula ##STR16## which still contains triethanolamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[O:10][CH2:12][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(F)c(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2cc(F)c(F)cc2N1
Yield: 63.7 %

Procedure:
A crude of 2-amino-4,5-difluorophenol (2.67 g, 18.4 mmol), 2-chloroacetyl chloride (2.28 g, 20 mmol) and K2CO3 (5.34 g, 38.6 mmol) were mixed according to GP1. Purified by column chromatography (SiO2; heptanes/EtOAc 4:1 to 1:1) to give the title compound (2.17 g, 64%). Rf=0.43 (heptanes/EtOAc 1:1); Mp=214.5-219.2° C.; 1H NMR (CD3OD) δ 6.90 (dd, J=11.4 Hz, J=7.2 Hz, 1H), 6.80 (dd, J=11.0 Hz, J=7.7 Hz, 1H), 4.56 (s, 2H); 13C NMR (CD3OD) δ 167.0, 147.0 (dd, J=243.5 Hz, J=13.8 Hz), 146.9 (dd, J=240.0 Hz, J=13.8 Hz), 141.2 (dd, J=9.8 Hz, J=3.0 Hz), 124.8 (dd, J=8.7 Hz, J=3.0 Hz), 106.9 (dd, J=22.0 Hz, J=6.9 Hz), 105.5 (dd, J=23.1 Hz, J=4.6 Hz), 68.1 (t, J=6.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=[O:14])[CH:3]=1.[BH4-].[Na+].O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][OH:14])[CH:3]=1
Reactant: O=Cc1sccc1-c1cc(Cl)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1sccc1-c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (30 mg, 0.13 mmol) in EtOH (1 mL) was added NaBH4 (50 mg, 1.3 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight, then was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated to yield [3-(4-chloro-pyridin-2-yl)-thiophen-2-yl]-methanol as an oil.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10]([N:12]=CN(C)C)=[N:9][C:8]=1[CH3:17])=O.[N+]([O-])(O)=O.[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:12][C:10]1[S:11][C:7]([C:5]2[CH:4]=[CH:3][N:38]=[C:36]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:34][CH:33]=3)[N:37]=2)=[C:8]([CH3:17])[N:9]=1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Solvent: O=[N+]([O-])O
Product: Cc1nc(N)sc1-c1ccnc(Nc2ccc(N3CCOCC3)cc2)n1

Procedure:
By condensation between N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (prepared from 1-(2-amino-4-methyl-thiazol-5-yl)-ethanone and N,N-dimethylformamide dimethylacetal) and N-(4-morpholin-4-yl-phenyl)-guanidine nitrate. Yellow solid. M.p. 300-304° C.: 1H-NMR (DMSO-d6) δ: 2.46 (s, 3H, CH3), 3.07 (m, 4H, CH2), 3.76 (m, 4H, CH2), 6.85 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 6.92 (m, 2H, Ph-H), 7.53 (br. s, 1H, NH), 7.67 (m, 2H, Ph-H), 8.30 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.25 (br. s, 1H, NH). MS (ESI+) m/z 369 [M+H]+ (C18H20N6OS requires 368.5).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C@H:8]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@:10]([CH:35]=[O:36])([CH2:11][CH2:12][C:13]3[C@H:14]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:17]([C@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]4)[CH2:9]1.O.[OH-].[Na+]>O1CCCC1>[OH:36][CH2:35][C@:10]12[CH2:9][C@@H:8]([OH:7])[CH2:32][CH2:31][C@:30]1([CH3:33])[C:29]1[CH2:28][CH2:27][C@@:26]3([CH3:34])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:13]=1[CH2:12][CH2:11]2
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@]1(C=O)CC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@]1(CO)CC3
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 39.8 %

Procedure:
A suspension of 56 mg lithiumaluminum hydride in 5 ml tetrahydrofuran is added to a solution of 200 mg 3β-hydroxy-5α-cholest-8-en-5-carbaldehyde in 20 ml tetrahydrofuran at room temperature. After being heated to 50° C. for two hours the reaction mixture is cooled to room temperature, 0.06 ml water, 0.06 ml of a sodium hydroxide solution (1 N) and 0.18 ml water are added subsequently. The resulting suspension is stirred for 15 minutes and filtered over anhydrous sodium sulphate. After evaporation of the solvent the residue is crystallized from ethylacetate to give 80 mg 5-(hydroxymethyl)-5α-cholest-8-en-3β-ol as a white solid.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][N:25]([CH3:34])[C:26](=[O:33])[CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30]>N1C=CC=CC=1.[Cu-]=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:28]([CH2:27][C:26]([N:25]([CH3:34])[CH3:24])=[O:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: CN(C)C(=O)CNS(C)(=O)=O
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Agent: O=[Cu-]
Solvent: c1ccncc1
Product: CN(C)C(=O)CN(c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12)S(C)(=O)=O
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide (0.57 g, 1.5 mmol), N,N-dimethyl-2-[(methylsulfonyl)amino]acetamide from Step 1 (0.25 g, 1.38 mmol) and copper (I) oxide (0.10 g, 0.70 mmol) in pyridine (5 mL) was heated in an oil bath at 115° C. overnight. The resultant mixture was concentrated under vacuum. To the residue, chloroform (200 mL) and a saturated aqueous solution of ethylenediamine tetraacetic acid, disodium salt (75 mL) was added. The mixture was stirred vigorously at room temp for 2 hours in the presence of air, and filtered through a pad of Celite. The organic extract was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:16])=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:16][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)[CH:7]=2)=[CH:14][N:13]=[C:12]([NH2:15])[CH:11]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(N)ncc1Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 60.7 %

Procedure:
5-(2-chloropyridin-4-yloxy)-4-methylpyridin-2-amine (0.116 g, 0.492 mmol) was dissolved in DMF (2 ml) and 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (0.154 g, 0.738 mmol) was added, followed by cesium carbonate (0.481 g, 1.477 mmol) and water (0.667 ml). Argon was bubbled through the mixture for several minutes, and then palladium tetrakistriphenylphosphine (0.028 g, 0.025 mmol) was added. The flask was fitted with a reflux condenser, flushed with argon, and heated under a balloon of argon at 90° C. for 16 hours. The mixture was then cooled to RT, and the solution was diluted with a 4:1 mix of ethyl acetate and THF (70 mL). It was washed with 10% aqueous LiCl (2×50 mL) and brine (50 mL), dried (MgSO4), evaporated in vacuo and purified via silica gel chromatography (DCM/MeOH) to yield 4-methyl-5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amine as a clear oil (0.084 g, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.11 (d, 1H), 6.50 (dd, 1H), 6.38 (s, 1H), 5.89 (s, 2H), 3.84 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z: 282.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18].[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:14]([C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:20][CH3:21])=[C:3]([C:17](=[O:19])[CH3:18])[CH:4]=2)[O:9][C:8]([CH3:13])([CH3:12])[CH:7]=1)([CH3:15])[CH3:16]
Reactant: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2C(C)C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2

Procedure:
As described in General Procedure A, a solution of 1-(7-hydroxy-4 isopropyl-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 62, 205 mg, 0.69 mmol) in acetone were added ethyl iodide (0.3 mL, 3.45 mmol) and potassium carbonate (476 mg, 3.45 mmol) to give rise to the title compound as a colorless oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexanes).