Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:23]=[CH:22][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)O1.I[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[N:28]([C@H:36]2[CH2:41][CH2:40][C@@H:39]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[N:27]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([C@H:36]3[CH2:41][CH2:40][C@@H:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:38][CH2:37]3)[N:27]=[C:26]([C:9]3[CH:10]=[CH:11][C:12]([O:13][C:14]4[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=4)=[CH:22][CH:23]=3)[C:34]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)cc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C#N)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzonitrile (2.63 g, 0.00819 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.01 g, 0.00683 mol), tetrakis-(triphenylphosphine)palladium (0.473 g, 0.00041 mol) and sodium carbonate monohydrate (2.12 g, 0.0171 mol) was heated in a mixture of ethylene glycol dimethyl ether (80 mL) and water (40 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice (100 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (96:3:1) as a mobile phase to give cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile (2.45 g, 0.00483 mol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:16]=[C:15]([C:17]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)=O)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[CH2:25]([SH:28])[CH2:26][SH:27].B(F)(F)F.CCCCOCCCC>ClCCl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:16]=[C:15]([C:17]2([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[S:28][CH2:25][CH2:26][S:27]2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccco2)c1
Reactant: SCCS
Agent: FB(F)F
Solvent: CCCCOCCCC
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C2(c3ccco3)SCCS2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Dissolve 5-(furan-2-carbonyl)-N-methyl-N-propyl-isophthalamic acid methyl ester (290 mg, 0.88 mmol) in dichloromethane (2 mL). Cool to 0° C., add a solution of ethane-1,2-dithiol (0.22 mL, 2.2 mmol) and then add a solution of boron trifluoride dibutyl etherate (0.66 mL, 5.2 mmol) in dichloromethane (5 mL). Warm the mixture to room temperature and stir overnight. Quench with water and dilute with dichloromethane. Wash the organic layer by saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 30:70 ethyl acetate:hexanes) to give the title compound (38%).
Reaction SMILES: [CH3:1][C:2]([O:6][OH:7])([CH:4]=[CH2:5])[CH3:3].[CH3:8][C:9](O)([CH:11]=[CH2:12])[CH3:10].S(=O)(=O)(O)O.CCCCCC>O>[CH3:1][C:2]([O:6][O:7][C:9]([CH3:10])([CH:11]=[CH2:12])[CH3:8])([CH:4]=[CH2:5])[CH3:3]
Reactant: C=CC(C)(C)OO
Reactant: C=CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: O
Product: C=CC(C)(C)OOC(C)(C)C=C
Temperature: 30 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
A mixture of 21.0 g of 2-methyl-3-buten-2-yl hydroperoxide and 17.2 g of 2-methyl-3-buten-2-ol was added, with stirring, to 80 g of a solution of 40% by weight-sulphuric acid in water over a period of 30 minutes and at a temperature of 20° C. Subsequently, the reaction mixture was stirred for 4 hours at 30° C. After the mixture had been cooled 50 ml of water and 50 ml of hexane were added. The organic phase was separated and washed with aqueous sodium hydroxide and, finally, with water. After the hexane had been distilled off under reduced pressure 22.5 g of colourless liquid were obtained. This liquid was then purified by fractional distillation, which resulted in 11.3 g of colourless liquid having a peroxide 2 content determined by G.L.C. of 75%.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH:4]=1)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[CH2:37][OH:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[OH:38][CH2:37][C@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:24][CH2:25]2)[CH:4]=1
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: OC[C@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5CO)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added (2R)-2-pyrrolidinylmethanol (101.15 mg, 1 mmol) and 2 drops of acetic acid. The resulting mixture was stirred at room temperature for 4 h followed by an addition of sodium triacetoxyborohydride (212 mg, 0.54 mmol). The mixture was reacted overnight. It was then purified by Gilson Preparatory HPLC to give 20.5 mg of the title compound (69.7%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:18].[Br:19]Br>CC(O)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:19])=[CH:4][C:3]=1[CH3:18]
Reactant: BrBr
Reactant: Cc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Solvent: CC(=O)O
Product: Cc1cc(Br)c2c(c1N)C(=O)c1ccccc1C2=O
Temperature: 40 °C
Yield: 90 %

Procedure:
1-amino-2-methylanthraquinone (300 g) is slurried with 1500 ml of HOAc in a 5-liter flask. The temperature is raised to 40° C. Neat bromine (405 g) is added over 21/2 hours with stirring at 40°-50° C. The mixture is stirred for 20 additional minutes and filtered. The solids so recovered are washed with HOAc and water and sucked dry with an aspirator and transferred to a reaction flask along with 150 g of NaHSO3 and 1.5 liters of water. The mixture is gradually heated to 90° C. (over two hours) with stirring to give 1-amino-2-methyl-4-bromoanthraquinone as a solid which is recovered from the reaction mixture by filtration in 90% yield, rinsed with water and dried overnight at 155° C. and 1 mm Hg absolute vacuum.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Mg]Br>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH3:11])[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: O=Cc1cccc(Br)c1F
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccccc1C(O)c1cccc(Br)c1F
Temperature: -78 °C
Yield: 80 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF (21.42 mL) cooled to −78° C. was added (2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, and then allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and additional (2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol) was added. The mixture was allowed to warm to room temperature overnight. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with DCM. The layers were separated and the aqueous phase extracted twice with DCM. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of DCM and purified via silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-0% EtOAc in hexanes over 27 min, tr=19 min) gave the title compound (1.22 g, 3.92 mmol, 80% yield) as a pale yellow liquid. 1H NMR (400 MHz, CD3OD) δ 7.54-7.40 (m, 2H), 7.35-7.23 (m, 2H), 7.09-6.90 (m, 3H), 6.38 (s, 1H), 4.12 (q, J=7.0 Hz, 1H), 3.76 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,3,4-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (51.9 mg) with purity >90%. MS (pos) m/z 429.0, 431.0, 433.0.
Reaction SMILES: [CH:1]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=2[Cl:17])[C:13]([C:18]([OH:20])=[O:19])=[CH:12][CH2:11]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Ni]>[CH:1]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=2[Cl:17])[CH:13]([C:18]([OH:20])=[O:19])[CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: O=C(O)C1=CCc2cc(C3CCCCCC3)c(Cl)cc21
Agent: [Ni]
Solvent: CCO
Product: O=C(O)C1CCc2cc(C3CCCCCC3)c(Cl)cc21

Procedure:
A solution of 1 g of 5-cycloheptyl-6-chloro-ind-1-ene-1-carboxylic acid in 40 ml of absolute ethanol is hydrogenated with 100 mg of Raney nickel at room temperature and normal pressure until 1 equivalent of hydrogen has been taken up. The catalyst is then filtered off, the filtrate is evaporated to dryness in vacuo and the residue is crystallised from ether/petroleum ether. 5-Cycloheptyl-6-chloro-1-indanecarboxylic acid, thus obtained, melts at 138°-140°C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:21])([F:20])[C:9]1[NH:19][C:12]2=[N:13][CH:14]=[C:15]([CH2:17][NH2:18])[CH:16]=[C:11]2[CH:10]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>CS(C)=O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:18][CH2:17][C:15]2[CH:16]=[C:11]3[CH:10]=[C:9]([C:8]([F:7])([F:20])[F:21])[NH:19][C:12]3=[N:13][CH:14]=2)[CH:28]=1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: FC(F)(F)c1cc2cc(CNc3cc(Cl)ncn3)cnc2[nH]1
Temperature: 120 °C

Procedure:
Potassium carbonate (106 mg, 0.767 mmol) was added to 1-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 75 mg, 0.349 mmol) and 4,6-dichloropyrimidine (104 mg, 0.697 mmol) in DMSO (2 mL). The mixture was heated at 120° C. for 1 hour in the microwave. Crude LCMS showed desired product and no starting material left so the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL), brine (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. This solid was dissolved in a mixture of acetonitrile and DMSO (1:1, 1.8 mL) and purified by MDAP. Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a brown solid (24 mg);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[C:23]1[CH:28]=[CH:27][N:26]=[N:25][CH:24]=1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][N:26]=[N:25][CH:24]=1
Reactant: Brc1ccnnc1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Cl)c(-c2ccnnc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
[2-Chloro-5-(trifluoromethyl)phenyl]boronic acid (0.410 g, 1.83 mmol), caesium carbonate (1.1 g, 3.38 mmol) and 4-bromopyridazine hydrobromide (Preparation 20, 0.35 g, 1.46 mmol) were dissolved in 1,4-dioxane (3.5 mL) and water (1 mL). The mixture was heated to 80° C. under nitrogen then palladium tetrakis triphenylphosphine (0.085 g, 0.074 mmol) was added. The reaction was stirred for three hours before it was left to cool to room temperature. The mixture was subsequently filtered through Arbocel®, then diluted in ethyl acetate (15 mL) and washed twice with a saturated solution of aqueous brine (15 mL). The organic layer was collected, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ISCO™, 0-50% ethyl acetate in heptane gradient elution, 12 g SiO2) to give title compound as a green solid (0.23 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:33])[CH2:14][CH2:15][CH2:16][S:17]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH:37]([CH3:39])[CH3:38]>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:33])[CH2:14][CH2:15][CH2:16][S:17]([N:20]([CH:37]([CH3:39])[CH3:38])[C:21]2[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(C)CCCS(=O)(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1OC
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CCN(C)CCCS(=O)(=O)N(c2cc(OC)c(OC)c(OC)c2)C(C)C)cc1OC
Yield: 46.6 %

Procedure:
3-[[2-(3,4-Dimethoxyphenyl)ethyl]methylamino]-N-(3,4,5-trimethoxyphenyl)-1-propanesulfonamide (6.7 g, 0.0139 mol) in dry dimethylformamide (100 mL) was treated with sodium hydride, 60% in mineral oil, (0.555 g, 0.0139 mol) and the reaction stirred 1 hour at which point 2-bromopropane (1.71 g, 0.0139 mol) was added and the solution warmed overnight. The reaction was then stripped, dissolved in methylene chloride, filtered and evaporated to a gum. Preparative high pressure chromatography provided the title compound (3.40 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2C=NC(C)=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:37])[C:19]([N:21]3[CH2:30][CH2:29][C:28]4[C:27]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)=[N:26][CH:25]=[N:24][C:23]=4[CH2:22]3)=[O:20])[C:4]=12.Cl.[N:39]1C=CC=[CH:41][C:40]=1C1C2CCNCC=2N=CN=1.COC1C=NC(N2C=CN=N2)=C2NC=C(C(=O)C(O)=O)C=12>>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:41]=[CH:40][N:39]=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:37])[C:19]([N:21]3[CH2:30][CH2:29][C:28]4[C:27]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)=[N:26][CH:25]=[N:24][C:23]=4[CH2:22]3)=[O:20])[C:4]=12
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Agent: COc1cnc(-n2ccnn2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: Cl
Product: COc1cnc(-n2ccnn2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12

Procedure:
The procedure described in Part E of preparation of compound 18 above was employed for the coupling of 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride with 2-(4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid to afford 1-(4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione; HRMS: 486.1677 (M+H)+ [calc'd: 486.1684]; 1HNMR (500 MHz, DMSO-d6) δ 12.82 (br s, 1H), 9.18 (s, 2/3H), 9.09 (s, 1/3H), 8.95 (s, 1H), 8.78 (m, 1/3H), 8.68 (m, 2/3H), 8.34 (s, 2/3H), 8.26 (s, 1/3H), 8.12-8.01 (m, 3H), 7.97 (s, 1H), 7.58 (m, 1/3H), 7.53 (m, 2/3H), 4.93 (s, 4/3H), 4.73 (s, 2/3H), 3.96 (s, 1H), 3.93 (m, 2/3H), 3.90 (s, 2H), 3.70 (m, 4/3H), 3.32 (m, 2/3), 3.18 (m, 4/3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([C:21]#[N:22])[CH:15]=3)=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:21]([C:16]1[CH:15]=[C:14]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=3)[N:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=2)[N:18]([CH2:19][CH3:20])[N:17]=1)#[N:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc(N)ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc(NS(C)(=O)=O)ccc12
Yield: 90.4 %

Procedure:
Stir a solution of 5-(6-Amino-1-isopropyl-1H-indol-3-yl)-1-ethyl-1H-pyrazole-3-carbonitrile (0.126 g, 0.393 mmol), pyridine (0.062 g, 0.786 mmol) and methanesulfonyl chloride (0.068 g, 0.590 mmol) in methylene chloride (3 mL) at room temperature for 2.5 h. After this time, Purify the reaction directly by chromatography (silica, methylene chloride to 1:9 ethyl acetate/methylene chloride) then freeze-dried from acetonitrile/water to afford N-[3-(5-Cyano-2-ethyl-2H-pyrazol-3-yl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (0.132 g, 90%) as alight purple solid: mp 144-145° C.; 1H NMR (500 MHz, DMSO-d0.6 δ0.60 (s, 1H), 7.84 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.11 (s, 1H), 7.04 (dd, J=8.5, 1.5 Hz, 1H), 4.73 (m, 1H), 4.27 (q, J=7.0 Hz, 21H), 2.96 (s, 3H), 1.52 (d, J=6.5 Hz, 6H), 1.35 (t, J=7.0 Hz, 3H) LCMS (Method 4)>99%, 6.96 min, m/z 372 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1.[H-].[Na+].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:21]=1[C:22]#[N:23]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([CH2:12][O:13][C:24]2[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[C:21]=2[C:22]#[N:23])[CH2:10][CH2:11]1
Reactant: N#Cc1c(F)cccc1F
Reactant: OCC1CCC(Cc2cccc(Cl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCC1CCC(Cc2cccc(Cl)c2)CC1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
[4-(3-Chlorobenzyl)cyclohexyl]-methanol (150 mg; 0.63 mmol) was added to a suspension of sodium hydride (33 mg; 0.82 mmol) in 3 mL of dimethylformamide at 0° C. After 2 hours, mixture was added to a mixture of 2,6-difluorobenzonitrile (88 mg; 0.63 mmol) in 2 mL of dimethylformamide at 0° C. After 16 hours mixture was quenched with 5 g of ice. Aqueous mixture was extracted with 5×15 mL of ethyl acetate. Combined ethyl acetates were washed with 6×15 mL water, brine and dried over MgSO4. Residue was purified via flash chromatography using 5-15% ethyl acetate in hexanes gradient to give 173 mgs of title compound. (77% yield).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](Cl)[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].O.[NH2:24][NH2:25]>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:24][NH2:25])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: FC(F)(F)c1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc(C(F)(F)F)ccc2n1

Procedure:
In the manner given in Example 1, 6-(trifluoromethyl)-2-chloro-4-(o-chlorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 6-(trifluoromethyl)-4-(o-chlorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: O=[O+][O-].[CH2:4]([N:7]([CH2:15][C:16]([O:18]C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=C.[NH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=2[CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH:21]([N:20]1[CH2:5][CH2:4][N:7]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:15][C:16]1=[O:18])[CH2:30][CH2:29]2)#[N:32]
Reactant: N#Cc1ccc2c(c1)CCC(N)C2
Reactant: C=CCN(CC(=O)OC)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCc3cc(C#N)ccc3C2)C(=O)C1
Temperature: 25 °C

Procedure:
Ozone was bubbled into a solution of methyl [allyl(tert-butoxycarbonyl)amino]acetate (3.6 g, 16 mmol) in DCM at −78° C. until it turned pale blue. Nitrogen was then bubbled into the solution to remove excess ozone. When the blue color was gone, 6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (2.7 g, 16 mmol) and sodium triacetoxyborohydride (20 g, 95 mmol) was added to the reaction, and the mixture was allowed to warm to RT. The reaction was diluted with DCM, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and purified by preparative TLC to afford the title compound. LC-MS (IE, m/z): 256 [M−Boc+1]+.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[Cl:29][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[S:8][CH:9]=2)=[CH:15][CH:16]=1
Reactant: OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of [4-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.35 g), tetrahydrofuran (50 mL) and toluene (50 mL) was added a solution (5 mL) of thionyl chloride (1.5 mL) in toluene under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give colorless crystals (4.10 g, 89%) of 4-(4-chloromethylphenoxymethyl)-2-phenylthiazole. melting point: 98-99° C.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[N:12]=[CH:11]2.CI>CN(C=O)C>[CH3:1][O:22][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([I:7])=[CH:16][CH:15]=3)[CH:11]=[N:12]2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
K2CO3 (7.35 g, 53.2 mmol) is suspended in 110 mL DMF. 4-(5-iodoindazole-1-yl)-benzoic acid (17.6 g, 48.33 mmol), dissolved in 25 mL DMF, is added dropwise. The reaction mixture is stirred for 30 min at r.t. Subsequently CH3I (3.31 mL, 53.2 mmol) is added dropwise (temperature rises to 30° C.). The reaction mixture is stirred overnight at r.t. and then poured on ice water. It is three times extracted with ethyl acetate. The combined organic extracts are washed twice with water and brine. After drying over Na2SO4 and filtration the solvent is evaporated. The residue is purified by chromatography (silicagel, eluents: ethyl acetate/hexane) yielding 14.03 g (76.8%) of the title compound.