Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][NH2:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:8][CH2:9][CH2:10][NH2:11]
Reactant: NCCN
Reactant: Brc1ccccn1
Product: NCCNc1ccccn1
Yield: 14.2 %

Procedure:
2-Bromopyridine (10.00 g, 63.3 mmol) was added dropwise to 1,2-diaminoethane (76.00 g, 126.6 mmol) under nitrogen at 20° C. with stirring. The reaction mixture was stirred at 20° C. for 4 h. and then under reflux for 24 h. The reaction mixture was concentrated in vacuo and purified by column chromatography on flash silica eluting with dichloromethane, ethanol and ammonia (30:8:1) to afford the title compound as a red oil (1.23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[CH3:10][N:11]1[C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CCCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:15]2[N:11]([CH3:10])[N:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: Nc1ccc(Cl)cc1I
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cn1nccc1-c1cc(Cl)ccc1N
Temperature: 70 °C
Yield: 73.6 %

Procedure:
A 250-mL round-bottom flask was charged with 4-chloro-2-iodoaniline (6.189 g, 24.42 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.62 g, 36.6 mmol), potassium carbonate (13.50 g, 98 mmol), and PdCl2(dppf)-CH2Cl2 (0.997 g, 1.221 mmol). The flask was flushed with Ar, then 1,4-dioxane (61.0 ml) and water (20.35 ml) were added in sequence. A reflux condenser was attached, and the flask was heated to 70° C. for 4 h. After being cooled to room temperature, the mixture was diluted with water and EtOAc (a small amount of brine was added to clear the emulsion). The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by chromatography on silica gel (30 to 80% EtOAc/Heptane). The partially purified product was taken up in a boiling mixture of heptane (100-mL) and EtOAc (5 mL) to give an opaque solution. A 250-mL flask containing the solid was charged with heptane (100 mL). The mixture was cooled to room temperature after 3 h, then the solid was collected by filtration, washed with heptane (3×50 mL), and dried under a stream of N2 for 20 min to give 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)aniline (3.732 g, 17.97 mmol, 73.6% yield) as a light purple solid. 1H NMR (400 MHz, DMSO-d6) δ=7.50 (d, J=1.9 Hz, 1 H), 7.16 (dd, J=2.6, 8.7 Hz, 1 H), 7.02 (d, J=2.5 Hz, 1 H), 6.78 (d, J=8.7 Hz, 1 H), 6.29 (d, J=1.8 Hz, 1 H), 5.07 (s, 2 H), 3.65 (s, 3 H). m/z (ESI) 208.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)=[CH:9][N:8]=1>C1COCC1>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[O:15][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[C:7]([S:5][CH2:3][CH3:4])=[N:8][CH:9]=1
Reactant: N#Cc1cc(Oc2ccc(Cl)c(Cl)c2)cnc1Cl
Reactant: CCS
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCSc1ncc(Oc2ccc(Cl)c(Cl)c2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
THF (25 ml), and NaOH (0.8 g) were mixed in a reaction flask to which was added 1.24 g of ethanethiol (previously chilled in an ice-salt bath). This mixture was stirred at room temperature until all of the NaOH was dissolved. Separately, 4.5 g of 2-chloro-5-(3,4-dichlorophenoxy)-3-pyridinecarbonitrile was dissolved in 25 ml of THF and then added to the previously prepared ethanethiol mixture. This combination was then stirred at room temperature for 30 minutes and then heated to boiling for 2 hours after which it was allowed to cool and then poured into 300 g of ice. A precipitate formed which was collected by filtration and subsequently recrystallized from a CH2Cl2 /hexane mixture to give 4.3 g of the desired 5-(3,4-dichlorophenoxy)-2-ethylthio-3-pyridinecarbonitrile, m.p. 80°-81° C.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[CH:12]2.[CH2:20](I)[CH3:21]>O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[CH:13]=[CH:12]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ccc2cc(Br)ccc2c1=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 22 mg of 60% sodium hydride was added at 0° C. to 3 ml solution of dimethylformamide with 100 mg of 6-bromo-2H-isoquinoline-1-one, and the mixture was stirred for 30 min. 0.04 ml of ethyl iodide was added at 0° C., and the mixture was stirred at room temperature for 3 hours. Cold water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by thin-layer chromatography (hexane/ethyl acetate=3/1) to obtain 30 mg of the above compound as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[O:10][C:9](=[O:14])[C:8]=2[CH:15]=1.[CH3:16]I>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH3:16])[C:11](=[O:13])[O:10][C:9](=[O:14])[C:8]=2[CH:15]=1
Reactant: CI
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
As illustrated in the scheme above, NaH (2.43 g of a 60% dispersion, 60.8 mmol) was added to a solution of 6-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (10.0 g, 50.6 mmol) dissolved in DMF (200 mL). The resulting mixture was stirred at room temperature for 30 min., and then methyl iodide (6.3 mL, 101 mmol) was added dropwise. After the reaction had stirred at room temperature overnight, it was concentrated in vacuo. Water and brine were added to the residue, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with 3:1 hexanes:EtOAc. The solvent was removed by filtration, and the resulting solid was washed with additional 3:1 hexanes:EtOAc, followed by 100% hexanes. The product was dried briefly under vacuum to produce the title compound as a pale yellow solid. (8.59 g, 80%). 1H-NMR (DMSO-d6): δ 7.96 (d, J=2.6 Hz, 1H), 7.89 (dd, J=2.6 Hz, J=9.0 Hz, 1H), 7.48 (d, J=9.0 Hz, 1H), 3.45 (s, 3H). MS (ESI) (M+H)+=212.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[Br:8][C:9]([CH3:14])([CH3:13])[C:10](Br)=[O:11]>C1COCC1>[Br:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[O:11]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-dimethylaminopropylamine (25 ml, 0.1 mol) in THF (50 ml) was added dropwise over 50 minutes and while keeping the temperature between 0-10° C. bromoisobutyroyl bromide (23.0 g, 0.1 mol). The mixture is stirred for another 3 h at room temperature and the THF is then evaporated in vacuo. Water (20 ml) is added to the residue and the mixture is extracted with t-butyl-methyl ether (2×30 ml) and ethylacetate (30 ml).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12](Br)=[CH:13][CH:14]=2)[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:22][CH:23]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1>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.C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][CH:23]([CH3:22])[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:28][CH:29]=3)=[CH:13][CH:14]=2)[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c2cc(Br)ccc12
Reactant: CC(C)CCCC(C)CCOc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(=O)OCC)c2cc(-c3ccc(OCCC(C)CCCC(C)C)cc3)ccc12
Yield: 54.1 %

Procedure:
Under argon atmosphere and in a toluene/water mixed solvent, 6-bromonaphthalene-1,4-dicarboxylic-acid diethyl ester 4.5 g and 4-(3,7-dimethyloctyloxy)phenyl boric acid 4.0 g were reacted with using tetrakis(triphenylphosphine)palladium under a condition of usual Suzuki reaction. Purification by column treatment (silica gel/toluene) was carried out, and 6-(4-(3,7-dimethyloctyloxy)phenyl)naphthalene-1,4-dicarboxylic-acid diethyl ester 3.5 g was obtained.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7](O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].P(Br)(Br)[Br:12]>>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([Br:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: BrP(Br)Br
Reactant: CCCC1CCC(O)CC1
Product: CCCC1CCC(Br)CC1
Temperature: 25 °C
Yield: 176 %

Procedure:
142 g (1.0 mol) of 4-propylcyclohexanol (trans-cis form mixture) was given drop addition of 136 g (0.5 mol) of PBr3 while stirring at room temperature, and heated to about 80° C. The reactant was stirred for 1 hour on a 70° C. hot water bath, then cooled to room temperature and poured into ice water to decompose the excess PBr3. The oily layer was taken off, and the water layer was extracted with chloroform, combined with the oily layer and washed with water. The chloroform was removed, and the remaining oily substance was distilled under reduced pressure (b. p. 97° C./14 mmHg) to obtain 180 g (0.88 mol) of 4-propylbromocyclohexane (trans-cis form mixture).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:5]2[N:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=13)[C:7]([C:14](OC)=[O:15])=[CH:6]2)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([C:3]1[C:12]2[N:13]3[C:8](=[C:7]([CH2:14][OH:15])[CH:6]=[C:5]3[C:4]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:9]=[CH:10][CH:11]=2)[CH3:2]
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(C(=O)OC)c3cccc1n32
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1c(-c2ccc(OC)cc2)c2cc(CO)c3cccc1n32
Yield: 83 %

Procedure:
The general synthetic pathway outlined in example 1 have been applied to proper starting materials in the preparation of methyl 4-ethyl-3-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine-1-carboxylate, which was reacted with lithium aluminium hydride by the general synthetic principle outlined in example 1, step 4, to afford 1-ethyl-4-hydroxymethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine as yellow crystals in 83% yield. MS(SP): m/z 305 (M+). 1H-NMR (CDCl3, 200 MHz) δ: 1.47 (t, 3H); 3.24 (q, 2H); 3.90 (s, 3H); 5.18 (s, 2H); 7.09 (d, 2H); 7.57 (s, 1H); 7.65 (dd, 1H); 7.73 (d, 2H); 7.92 (d, 1H); 8.01 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Br:20]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[Br:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A slurry of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene 100 g (370 mmol) in 1 L of CHCl3 was heated to reflux then removed from the heat. A solution of 19.3 mL (370 mmol) of bromine in 170 mL of carbon tetrachloride was added dropwise as the solution slowly cooled to room temperature. The resulting mixture was concentrated to dryness in vacuo to yield 129 g of the title compound as brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH2:16]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[NH:16][CH2:15][CH2:14][CH2:13][O:12][CH3:11]
Reactant: COCCCN
Reactant: N#Cc1ccc(Cl)cc1F
Product: COCCCNc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 3-methoxy-propylamine analogously to the preparation of Intermediate 113.1. colorless oil; ES-MS: M−=227.1; HPLC: AtRet=2.97 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: N#Cc1ccc(N)cc1F
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C#N)c(F)c1
Temperature: 120 °C

Procedure:
2-Fluoro-4-aminobenzonitrile (11.8 g) and 1-bromohexadecane (15.3 g) are dissolved in hexamethylphosphoramide (200 ml.) and heated under an atmosphere of nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room temperature and water is added gradually. The mixture is then chilled in an ice-bath and filtered. The solid is washed thoroughly with water and dried. The solid is recrystallized from ether-hexane to yield 2-fluoro-4-(hexadecylamino)benzonitrile as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:10]O)[CH:6]=1)([F:4])[CH3:3].S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:10][C:7]1[CH:6]=[C:5]([C:2]([F:4])([F:1])[CH3:3])[O:9][N:8]=1
Reactant: CC(F)(F)c1cc(CO)no1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(F)(F)c1cc(CCl)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g of [5-(1,1-difluoroethyl)isoxazol-3-yl]methanol was dissolved in 10 ml of dichloromethane, and 0.8 ml of thionyl chloride was then added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 1.11 g of 3-(chloromethyl)-5-(1,1-difluoroethyl)isoxazole.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C@@:15]2([CH2:16][CH2:17][CH3:18])[C:10](=[CH:11][C:12](=[O:19])[CH2:13][CH2:14]2)[C:9]2[C:4]1=[CH:5][C:6]([O:22][CH2:23][C:24]([O:26]CC)=[O:25])=[C:7]([Cl:21])[C:8]=2[Cl:20]>C(O)C.O.[OH-].[Na+]>[NH2:2][CH:3]1[C@@:15]2([CH2:16][CH2:17][CH3:18])[C:10](=[CH:11][C:12](=[O:19])[CH2:13][CH2:14]2)[C:9]2[C:4]1=[CH:5][C:6]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[C:7]([Cl:21])[C:8]=2[Cl:20]
Reactant: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Ethyl [(9-amino-5,6-dichloro-3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetate hydrochloride (497.5 mg, 0.002 mole) is dissolved in a mixture of ethanol (17 ml), water (3 ml) and 1N sodium hydroxide (5 ml). The mixture is stirred at 25° C. for 10 hours, evaporated to dryness in vacuo and the residue dissolved in water (20 ml) and carefully neutralized with hydrochloric acid to the isoelectric points whereby a precipitate separates. The product is removed by filtration, washed with water and dried to give [(9-amino-5,6-dichloro-3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]1([CH:14]2[N:18]3[C:19](=[O:30])[N:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)C(O)[C@@H]3[CH2:16][S:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:8]1([CH:14]2[N:18]3[C:19](=[O:30])[N:20]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:6]3[CH2:16][S:15]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1N(Cc2ccccc2)C(O)[C@@H]2CSC(c3ccccc3)N12
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC1[C@@H]2CSC(c3ccccc3)N2C(=O)N1Cc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
33.69 g (0.33 mol) of acetic anhydride and 366.5 mg (3 mmol) of 4-(dimethylamino)-pyridine are added to a solution of 97.92 g (0.3 mol) of (7RS,7aR)-3-phenyl-6-benzyl-7,7a-dihydro-7-hydroxy-1H,3H-imidazo[1,5-c]thiazol-5(6H)-one in 900 ml of toluene, and the solution is stirred for 2 hours at 40° C. After cooling to room temperature the solution is washed with 180 ml of water, with 180 ml of a saturated sodium bicarbonate solution and the solvent is distilled off. 109.8 g of (7RS,7aR)-3-phenyl-6-benzyl-7,7a-dihydro-7-acetoxy-1H,3H-imidazo[1,5-c]thiazol-5-(6H)-one are obtained as an oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:16]Br.C(OCC)(=O)C>CC(N(C)C)=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:16][O:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: N#Cc1cncc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cncc(OCc2cc(F)cc(F)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
876 mg (2 eq) of sodium hydride is added gradually at 0° C. under nitrogen to a solution of 865 mg of 5-hydroxynicotinonitrile (7.2 mmol) in 15 mL of dimethylacetamide. The mixture is stirred 10 min at 0° C. before adding 2.24 g (1.5 aq) of 3,5-difluorobenzyl bromide. The mixture is placed under stirring for 2.5 additional hours before being diluted in an ethyl acetate fraction and being washed with aqueous fractions. The organic phases are isolated, dried and concentrated. The solid residue obtained is recrystallized in methanol to yield 1.1 g (68% of 5-(3,5-difluorobenzyloxy) nicotinonitrile in the form of a beige powder.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:24](OCCC(C)C)=O.Cl>C(Cl)(Cl)Cl.CO>[Cl:11][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]2[C:2]=1[NH:1][N:24]=[CH:10]2
Reactant: CC(C)CCON=O
Reactant: Cc1cc(C#N)cc(Cl)c1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 18.3 %

Procedure:
To a mixture of 4-amino-3-chloro-5-methyl-benzonitrile (3.0 g, 18.0 mmol) in chloroform (50 mL) was added acetic anhydride (3.92 mL, 41.4 mmol). The mixture was heated at reflux for 5 hours and then cooled to room temperature. To the mixture was added potassium acetate (530 mg, 5.4 mmol) and isoamyl nitrite (5.28 mL, 39.6 mmol). The reaction was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature, extracted with saturated aqueous sodium bicarbonate, the organics were dried over sodium sulfate, and concentrated in vacuo to afford a brown oil. The oil was dissolved in methanol (25 mL) and concentrated hydrochloric acid (25 mL) was added. The reaction was stirred at room temperature for 22 hours and the methanol was concentrated in vacuo. The remaining aqueous layer was adjusted to a pH of 7 and the resultant precipitate was filtered to afford a brown solid which was purified by flash chromatography using 50% dichloromethane in heptane as eluent to afford 7-chloro-1H-indazole-5-carbonitrile as a solid (585 mg, 18%): −ESI MS (M−1) 176.0; 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (br. s., 2H), 8.08 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]2[CH3:12].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[Cr+6].[O-2].[O-2]>[C:2]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]2[CH3:12])([OH:20])=[O:1]
Reactant: CCOC(=O)c1cc2c(CO)cccc2n1C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cc2c(C(=O)O)cccc2n1C
Temperature: 25 °C
Yield: 51.2 %

Procedure:
In 30 ml of acetone was dissolved 0.70 g (3.00 mmols) of ethyl 4-hydroxymethyl-1-methyl-2-indolecarboxylate. After 3.3 ml of Jones' reagent, which was prepared by dissolving 26.7 g of chromium (VI) oxide in a mixture of 23 ml of conc. sulfuric acid and 40 ml of water and adding water to make the whole volume 100 ml, was added dropwise to the above solution at room temperature, the mixture was stirred at room temperature for an hour. The reaction mixture was poured onto ice water and the aqueous layer was extracted three times with chloroform. The combined extracts were washed with saturated sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 0.38 g (51.2%) of ethyl 4-carboxy-1-methyl-2-indolecarboxylate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[S:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClC(Cl)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:24](=[O:25])[N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[N:12]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(NNC(=S)c2ccc(C(C)C)cc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(-n2nc(-c3ccc(C(C)C)cc3)sc2=O)cc1
Yield: 74.1 %

Procedure:
Methyl 4-{2-[(4-isopropylphenyl)carbonothioyl]hydrazino}benzoate (0.26 g, 0.8 mmol) and carbonyldiimidazole (0.19 g, 1.2 mmol) are stirred at 80° C. in dichloroethane (20 mL) overnight, and the mixture is subjected to chromatography directly (silica gel, 4:1 ethyl acetate-hexanes) to provide methyl 4-[5-(4-isopropylphenyl)-2-oxo-1,3,4-thiadiazol-3(2H)-yl]benzoate (0.21 g, 75%). MS (ES+): m/e 355.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH3:30])=[O:28])=[CH:23][CH:22]=3)=[C:15]([CH3:31])[CH:14]=2)[N:3]=1.[CH3:32][C:33]1[NH:37][N:36]=[C:35]([NH2:38])[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.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>[CH3:20][O:19][C:18]1[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:38][C:35]3[CH:34]=[C:33]([CH3:32])[NH:37][N:36]=3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][C:15]([CH3:31])=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH3:30])=[O:28])=[CH:23][CH:22]=2)[CH:17]=1
Reactant: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2C)cc1
Reactant: Cc1cc(N)n[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(C(F)(F)F)c(Nc4cc(C)[nH]n4)n3)cc2C)cc1
Temperature: 150 °C

Procedure:
The mixture of 4′-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide (Step 1, 20 mg, 0.044 mmol), 5-methyl-1H-pyrazol-3-amine (4.3 mg, 0.044 mmol), Xantophos (5.0 mg, 0.009 mmol), paladium acetate (II) (1.0 mg, 0.004 mmol), and cesium carbonate (28.6 mg, 0.088 mmol) in 2.0 mL of THF is heated at 150° C. in a microwave reactor for 25 min. The reaction mixture is filtered, the filtrate is concentrated in vacuo, and purified by preparative RP-HPLC to afford 5′-Methoxy-N,2′-dimethyl-4′-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)biphenyl-4-carboxamide; ESMS m/z 512.2 (M+H+).