Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][C:18](O)([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH2:17][CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.S(=O)(=O)(O)O.C(=O)(O)[O-:38].[Na+].[C:42](#[N:44])[CH3:43]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][C:18]([NH:44][C:42](=[O:38])[CH3:43])([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH2:17][CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ncnc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Reactant: CC#N
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ncnc2sc(NC(=O)N3CCC(NC(C)=O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of 4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (prepared in Example 65, 100 mg, 0.22 mmol) in acetonitrile (0.16 mL) and glacial acetic acid (0.21 mL) cooled to 0 C was treated dropwise with concentrated sulfuric acid (0.21 mL). The resulting mixture was then allowed to warm to 25° C. After stirring for 2 h, the reaction mixture was diluted with water, neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated in vacuo. High pressure liquid chromatography (acetonitrile/0.1% trifluoroacetic acid/water gradient) followed by lyophilization of the desired fractions afforded 4-acetylamino-4-(3-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (37 mg, 28%) as a white powder; ES-HRMS m/e calcd. for C21H22N6O3SF3 (M+H)+ 495.1421, found 495.1424.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[C:11]([Si](C)(C)C)#[N:12].[CH3:17][NH:18][CH2:19][CH2:20][OH:21]>CO.[I-].[Zn+2].[I-]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([N:18]([CH2:19][CH2:20][OH:21])[CH3:17])[C:11]#[N:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CNCCO
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Product: CN(CCO)C(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 10 g of 3,4-dichlorobenzaldehyde and 9.5 ml of cyanotrimethylsilane is cooled in an ice bath, 0.01 g of zinc iodide is added and the mixture is stirred for 15 minutes at RT. A solution of 4.5 g of 2-(methylamino)ethanol in 50 ml of MeOH is then added and the reaction mixture is heated at 60° C. for 2 hours. After one night at RT, it is concentrated under vacuum, the residue is extracted with ether and the organic phase is washed with water, dried over MgSO4 and filtered. The filtrate is acidified to pH 1 by the addition of a saturated solution of hydrochloric acid in ether, acetone is added and the mixture is stirred until crystallization occurs. This gives 15 g of the expected product after wringing of the crystals formed. M.p.=130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[CH3:14][NH:15][NH2:16].CCO>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH2:12])[N:15]([CH3:14])[N:16]=2)=[CH:4][CH:3]=1
Reactant: CNN
Reactant: N#CCC(=O)Cc1ccc(Cl)cc1
Solvent: CCO
Product: Cn1nc(Cc2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A solution of 4-(4-chlorophenyl)-3-oxo-butyronitrile (Preparation 96, 2.2 g, 11 mmol) and N-methylhydrazine (1.94 mL, 36.5 mmol) in EtOH (40 mL, 800 mmol) was heated at 100° C. in a 40 mL vial (the reaction was split into 2 equal batches). After 20 h, the reaction mixture was cooled to rt and concentrated in vacuo. The residue was purified on the Isco (40 g SiO2, hexanes to ethyl acetate) to afford the title compound as an off-white solid (1.83 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[N:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=1[O:12][C:14]1[CH:19]=[N:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(F)cc1Oc1ccc([N+](=O)[O-])nc1
Temperature: 110 °C

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (3.00 g), 5-chloro-2-nitropyridine (3.08 g), and potassium carbonate (4.87 g) were added to dimethyl sulfoxide (50 mL), heated to 110° C. for one hour, cooled, added to water, and extracted with ethyl ether. The ether was washed with brine and dried on anhydrous sodium sulfate. The solution was filtered and concentrated and purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes increasing to 20% ethyl acetate in hexanes and increasing again to 30% ethyl acetate in hexanes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[O:25].[CH3:37][NH2:38].C1COCC1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14]([NH:38][CH3:37])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[O:25]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cccc(C(F)(F)F)c4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cccc(C(F)(F)F)c4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 31.1 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (0.092 g, 0.18 mmol) and 2.00M MeNH2/THF (0.89 ml, 1.8 mmol) were combined to afford 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (28 mg, 31% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.61 (s, 1H), 8.12-8.09 (m, 2H), 8.04 (s, 1H), 7.68 s, 1H), 7.64 (brd, J=10.0 Hz, 1H), 7.50 (dd, J=7.6 and 16.0 Hz, 1H), 7.31 (brd, J=7.6 Hz, 1H), 7.06 (d, J=12.4 Hz, 1H), 6.82 (brs, 1H), 3.59 (s, 3H), 3.08 (brd, J=4.4 Hz, 3H), 2.16 (s, 3H); MS (ESI) m/z: 501.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2.[N+:14]([O-])([OH:16])=[O:15].O>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2
Reactant: O=[N+]([O-])O
Reactant: COc1cccc2c1C(=O)CCC2
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])c2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 8-methoxy-1-tetralone (2.26 g, 13 mmol) (prepared as described in Chatterjee, A. Tetrahedron, (1980), 36, 2513-2520) in acetic anhydride (11.5 mL) was cooled to 0° C., treated with a mixture of fuming nitric acid (0.90 mL) in acetic acid (0.70 mL) dropwise over 1 hour, stirred at 0° C. for 1.5 hours, treated with water (150 mL) and extracted with diethyl ether (300 mL). The diether ether layer was washed with water (150 mL), washed with sodium bicarbonate solution (3×), washed with brine, dried (MgSO4), filtered and concentrated. Purification of the residue on silica gel using a gradient of 2:1 and then 3:2 and finally 1:1 hexanes:ethyl acetate provided the desired product as the more polar isomer.
Reaction SMILES: C(OCC)(=O)C.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[S:28](Cl)([CH3:31])(=[O:30])=[O:29]>O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 5 °C

Procedure:
To 300 ml of an ethyl acetate solution containing 30.00 g of N-t-butoxycarbonyl-4-hydroxypiperidine and 41.6 ml of triethylamine was added dropwise 17.3 ml of mesyl chloride at −10° C. over 10 minutes. The temperature increased to 5° C. due to heat generation. After stirring with cooling in an ice bath for 10 minutes, 90 ml of water was carefully added dropwise to the reaction mixture. The temperature increased from 0° C. to 6° C. due to heat generation. After stirring for 10 minutes, the mixture was separated and the organic phase washed with water (90 ml×2), saturated saline (90 ml), water (90 ml) and saturated saline (90 ml) in this order. After drying with anhydrous magnesium sulfate, concentration was conducted under reduced pressure and 40.74 g of 1-t-butoxycarbonyl-4-mesyloxypiperidine was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:18])[N:14]=[CH:15][C:16](I)=[C:11]2[C:10]([CH3:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[C:25](=[O:27])=[O:26].[O-]S([O-])(=O)=O.[Ca+2]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:18])=[N:14][CH:15]=[C:16]([C:25]([OH:27])=[O:26])[C:11]=2[C:10]([CH3:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(I)c12
Reactant: O=C=O
Agent: CC(C)[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-chloro-4-iodo-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (2 g) in dry tetrahydrofuran (40 ml) was added 4 A molecular sieves. The solution was stirred at room temperature for 15 minutes then cooled to 40° C. Under an atmosphere of nitrogen was added dropwise, a solution of isopropylmagnesium chloride (2M in tetrahydrofuran, 5.4 ml) and the solution stirred at −40° C. for 10 minutes. The solution was saturated with a stream of carbon dioxide gas which had been passed through a column of Drierite and then diluted with ethyl acetate. The organic was extracted with 1N sodium hydroxide solution until complete extraction and the combined aqueous was then acidified to pH1 with concentrated hydrochloric acid. The acidified aqueous was extracted twice with ethyl acetate which was combined and washed with water until neutral. The ethyl acetate layer was then dried (MgSO4) and evaporated to give a solid. The solid was triturated with isohexane, filtered off and washed with isohexane. The solid was sucked dry then dried at 50° C. under vacuum to afford the title compound (1.22 g).
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[C:7]1([O:13][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Oc1ccccc1
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)Oc1ccccc1
Temperature: 110 °C
Yield: 43 %

Procedure:
The reaction flask was charged with 34.1 g (0.20 mole) of methylaminosulfonyl chloride, 18.8 g (0.20 mole) of phenol and 150 ml of toluene. The dark, red solution was heated at 110° C. for 16 hours. The solution was cooled and washed with a solution of 16 g of sodium bicarbonate in 80 ml water. The toluene solution was washed with water then stirred with Type 3A molecular sieve powder and Norite "A" activated charcoal. After filtration, the filtrate was concentrated to 32.7 g of oil (87% crude yield). The oil was dissolved in 100 ml methylene chloride and chromatographed on silica gel. The main fraction was concentrated to an oil which solidified after chilling for 3 days. The solid was triturated with petroleum ether to give 16.1 g of solid, mp 43°-45° C. A recrystallization from a mixture of isopropyl acetate (2 ml/g) and petroleum ether (4 ml/g) gave 12.3 g of solid, mp 44°-46° C.
Reaction SMILES: [CH2:1]([Si:4]([CH2:18][CH:19]=[CH2:20])([CH3:17])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].Br[C:22]1[C:35]2[C:26](=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=[N:28]3)[N:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O.CO>C1(C)C=CC=CC=1>[CH2:1]([Si:4]([CH2:18][CH:19]=[CH2:20])([CH3:17])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:22]2[C:35]3[C:26](=[C:27]4[C:32](=[CH:33][CH:34]=3)[C:31]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:30][CH:29]=[N:28]4)[N:25]=[CH:24][CH:23]=2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CC[Si](C)(CC=C)CCCc1ccc(B(O)O)cc1
Reactant: Brc1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: C=CC[Si](C)(CC=C)CCCc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Temperature: 100 °C

Procedure:
4-{3-[diallyl(methyl)silyl]propyl}phenylboronic acid is made by the method of Casado and Stobart (Casado, M. A.; Stobart, S. R., Org. Lett., 2 (11), 2000, 1549-1552). 4-{3-[diallyl(methyl)silyl]propyl}phenylboronic acid (0.576 g) and a solution of Pd(Ph3)4 (58 mg) in 5 mL of degassed toluene is placed in a 50 mL Schlenk tube. The mixture is purged with nitrogen, after which a solution of 4-bromo-7-phenyl-1,10-phenanthroline (0.670 g) and Na2CO3 (428 mg, 4 mmol) in 5 mL of degassed 4:1 H2O/CH3OH is added. The mixture is heated under nitrogen at 100° C. with rapid stirring until TLC monitoring shows the reaction to be complete (ca 24 hrs). The reaction mixture is then added to a separatory funnel and washed with ether (3×50 mL). The combined organic fractions are dried over MgSO4 and concentrated by roto-evaporation. The desired product is purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:44][C:45]([F:48])([F:47])[F:46])[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:44][C:45]([F:46])([F:47])[F:48])[N:17]=1
Reactant: C#Cc1ccccc1CC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)c(OC(F)(F)F)c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4CC(N)=O)n3)c(OC(F)(F)F)c2)CC1
Temperature: 120 °C
Yield: 73 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I41) (0.029 g, 0.18 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I48) (0.082 g, 0.15 mmol) in dry DMF (4 mL) were added triethylamine (0.085 mL, 0.61 mmol), triphenylphosphine (6.0 mg, 0.023 mmol), trans-dichlorobis (triphenylphosphine)palladium (II) (0.011 g, 0.015 mmol) and Cu(I)I (4.0 mg, 0.023 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I49) (0.073 g, 73% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 8.74 (s, 1H), 7.58 (dd, J=7.7, 6.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.42-7.27 (m, 5H), 6.99 (s, 1H), 4.14-4.03 (m, 2H), 3.67 (s, 2H), 2.87-2.72 (m, 3H), 1.79 (d, J=12.8 Hz, 2H), 1.50 (qd, J=12.5, 4.1 Hz, 2H), 1.42 (s, 9H). LCMS Method C: rt 6.63 min; m/z 564.0 [M-Boc+2H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2[C@H:28]1[CH2:30][C@H:29]1C(=C)C(OC)=O)#[N:8].[O:37]1CCC[CH2:38]1>>[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C@H:28]1[CH2:30][C@H:29]1[CH2:38][OH:37])#[N:8]
Reactant: C1CCOC1
Reactant: C=C(C(=O)OC)[C@@H]1C[C@@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3CO)c3cc(C#N)ccc32)cc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
Powdered lithium aluminum hydride (120 mg, 3.16 mmol) was carefully added to a stirred solution of methyl [cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cycloprop-1-yl]-acrylate (185 mg, 0.47 mmol) in anhydrous tetrahydrofuran (10 ml) at −30° C. The resulting mixture was stirred at −20° C. for 1.5 h. The reaction was quenched with ethyl acetate (5 ml) and allowed to warmed to room temperature. After 10 min, water (120 μL) was added and after 5 min followed by a solution of aqueous sodium hydroxide (1N, 360 μL). After a further 5 min water (120 ml) was added and the solution was stirred 20 min. The aluminum salts were removed by vacuum filtration. The salts were rinsed with ethyl acetate (100 ml) and the combined filtrates were concentrated in vacuo. The crude material was purified by silica gel column chromatography with 45% ethyl acetate in hexanes to afford 131 mg (76% yield) of cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropanemethanol as a white solid : 1H NMR (400 MHz, CDCl3): δ8.04 (1H, d, J=8.6 Hz), 7.99 (1H, d, J=1.0 Hz), 7.74 (2H, d, J=6.8 Hz), 7.57 (1H, dd, J=8.6, 1.6 Hz), 7.44 (1H, d, J=1.3 Hz), 7.26 (2H, d, J=8.2 Hz), 3.50 (1H, m), 3.16 (1H, m), 2.36 (3H, s), 2.05 (1H, m), 1.60 (1H, m), 1.19 (1H, m), 0.99 (1H, t, J=5.5 Hz), 0.72 (1H, q, J=5.6 Hz); MS m/e 349 (M−OH)−.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1C(O)=O)[CH:2]([CH3:4])[CH3:3].CN([C:17]([O:21]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:47][NH2:48]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:10][C:11]([C:17]([NH:47][NH2:48])=[O:21])=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: NN
Reactant: CC(C)Cc1ccccc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(C(=O)NN)cc1
Yield: 97.5 %

Procedure:
A solution isobutylbenzoic acid (2.00 g, 11.2 mmol) in DMF (10 ml) was treated with HBTU (4.25 g, 11.2 mmol), diisopropylethylamine (7.24 g, 56.0 mmol), then hydrazine (1.80 g, 56.0 mmol) and stirred at room temperature for 12 hours. The reaction was diluted with ethyl acetate (150 mL), washed with 5% NaHCO3 (aq.) and brine, dried (MgSO4), filtered and concentrated in vacuo to give the title compound (2.10 g, 91%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].C1N=CN([C:26]([N:28]2[CH:32]=[N:31][CH:30]=[CH:29]2)=[O:27])C=1.[O:33]1[CH2:38]CN(CCN)[CH2:35][CH2:34]1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:26]([NH:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:38][O:33][CH2:34][CH2:35]4)=[O:27])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: NCCN1CCOCC1
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)c1cc(-c2ccc3nc(NC(=O)NCCN4CCOCC4)sc3c2)cnc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (95 mg, 312 μmol) and CDI (110 mg, 678 μmol) in DMF (1 mL) was heated at 60° C. After sitting overnight, more reagent was added and the mixture was heated for 4 h. 2-morpholinoethanamine (300 μL, 2286 μmol) was added to the mixture, a solution formed. After 3 h, the mixture was cooled to rt and diluted with DCM (15 mL). The solution was washed with H2O (15 mL), dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography with 0-5% (2 N NH3-MeOH) in DCM to give the product as a white powder after hexane washing (45 mg, 31%). MS (ESI, POS. ION) M/Z: calc'd for C21H25ClN6O2S: 460.1. found: 461.1. 1H NMR (400 MHz, chloroform-d) δ ppm 2.49-2.70 (m, 6H) 2.92 (s, 6H) 3.49-3.59 (m, 2H) 3.71-3.83 (m, 4H) 7.49 (s, 1H) 7.56 (d, J=8.03 Hz, 1H) 7.79 (d, J=8.53 Hz, 1H) 7.90 (s, 1H) 8.24 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[C:16]([NH:26][C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:16]([NH:26][C@H:27]([C:31]([O:1][CH:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)C(C)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methoxybenzyl 2-hydroxypropionate (4.2 g, 20 mmole), N-CBZ-L-valine (5.02 g, 20 mmole) and DMAP (0.24 g, 2 mmole) in 100 ml dichloromethane was added a solution of DCC (4.54 g, 22 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled to 5° C. and the urethane was filtered. The filtrate was evaporated and the product was isolated by silica gel column chromatography. Yield: 7.9 g
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.O.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]2)[CH2:27][CH2:26]1>CO>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[CH:35]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CN1CCC(n2cc(N)cn2)CC1
Solvent: CO
Solvent: O
Product: CN1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 70 °C
Yield: 17 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.060 g, 0.21 mmol) in MeOH (1.0 mL) and water (0.1 mL) containing 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.039 g, 0.21 mmol) was heated at 70° C. for 48 hours. The mixture was adsorbed onto silica gel and purified by silica column chromatography (Combiflash Rf, 4 g SiO2 Cartridge, 0-50% MeOH in DCM). Further purification by HPLC (eluting with 30-100% gradient in acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid, flow rate 4.0 mL/min) gave the title compound 18 as a light yellow solid (0.015 g, 17%). LCMS-C: rt 4.31 min; m/z 480 [M+H]+.