Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2OCC#N)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[CH2:6][CH2:5][C:4]#[N:3])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4CCC#N)n3)cc21

Procedure:
3-{2-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenyl}-propionitrile was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (from Example 358a) in an analogous manner to Example 1221d. (120° C., 40 min). Obtained 83 mg (76%) as a white foam. HPLC purity: 90%, LCMS 461.22 (M+H), 1H-NMR (CDCl3, 400 MHz) δ: 8.09 (s, 1H), 7.46-7.42 (m, 1H), 7.41-7.31 (m, 4H), 7.28 (s, 1H), 7.05-6.92 (m, 3H), 4.00-3.20 (bm, 2H), 2.97 (t, J=7.2 Hz, 2 h), 2.61 (t, J=7.2 Hz, 2H), 2.28-2.22 (m, 2H), 2.22-2.2.05 (m, 2H), 1.00 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH3:13]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[CH3:13]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N)ccc1C

Procedure:
Compound 497 (26.5 g, 135.78 mmol) in ethanol (200 ml) was hydrogenated under 1 atmosphere at room temperature in the presence of Pd/C 5% (2.00 g) for 3 h. After reaction, the catalyst was filtered off. The filtrate was concentrated in vacuo, providing the title compound as a brownish oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][C:26]([C:31](O)=[O:32])=[CH:25][C:24]2=[O:34]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:26]1[O:27][C:28]2[C:23]([C:24](=[O:34])[CH:25]=1)=[CH:22][C:21]([Cl:20])=[CH:30][CH:29]=2)=[O:32]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1cc(=O)c2cc(Cl)ccc2o1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cc(=O)c2cc(Cl)ccc2o1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-chloro-4-oxo-4H-chromene-2-carboxylic acid. MS: 466.2 (M+H).
Reaction SMILES: [NH2:1][C:2]([CH3:55])([CH3:54])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH:16]([F:18])[F:17])=[CH:12][CH:13]=2)[C:8]([C:19]2[N:24]=[C:23]3[C:25]([C:47]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:26][N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[N:21][CH:20]=2)=[N:7]1.[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59]>ClCCl>[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59].[NH2:1][C:2]([CH3:55])([CH3:54])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH:16]([F:18])[F:17])=[CH:12][CH:13]=2)[C:8]([C:19]2[N:24]=[C:23]3[C:25]([C:47]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:26][NH:27][C:22]3=[N:21][CH:20]=2)=[N:7]1
Reactant: CC(C)(N)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)CCCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 2-(1-(4-amino-4-methylpentyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (54 mg, 0.08 mmol) in 3 mL of dichloromethane was added 3 mL of trifluoroacetic acid. The reaction mixture was stirred overnight at room temperature. After solvent evaporation, the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(1-(4-amino-4-methylpentyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide 2,2,2-trifluoroacetate (13 mg, 34%) as yellow solid. LCMS: (M+H)+=500; 1H NMR (300 MHz, CD3OD): δ 8.98 (s, 1H), 8.13 (s, 1H), 8.07 (d, 1H, J=2.1 Hz), 7.60 (d, 1H, J=9.3 Hz), 7.29 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 6.72 (t, 1H, J=74.1 Hz), 4.49-4.47 (m, 2H), 2.03-1.98 (m, 2H), 1.58-1.53 (m, 2H), 1.49 (s, 9H), 1.19 (s, 6H).
Reaction SMILES: [Na+].[CH2:2]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22](=[O:24])[NH2:23])[C:16]=2[C:15]2[C:10]1=[CH:11][C:12]([O:30][CH3:31])=[CH:13][C:14]=2[O:25][CH2:26][C:27]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[N:33](C)C=O.[H-].[Na+].BrCC#N>C(OCC)(=O)C.O1CCCC1>[CH2:2]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22]([NH2:23])=[O:24])[C:16]=2[C:15]2[C:10]1=[CH:11][C:12]([O:30][CH3:31])=[CH:13][C:14]=2[O:25][CH2:26][C:27]#[N:33])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc(OCC(=O)[O-])c2c3c(n(Cc4ccccc4)c2c1)CCCC3C(N)=O
Reactant: CN(C)C=O
Agent: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OCC#N)c2c3c(n(Cc4ccccc4)c2c1)CCCC3C(N)=O

Procedure:
A solution of 1.47 gram (4.19 mmol) of the product from Example 3, Part A in 146 ml. of dimethylformamide and 31 ml. tetrahydrofuran was treated with 210 mg. of sodium hydride (60% in mineral oil; 5.24 mmol) for 10 minutes and then with 0.39 ml. (0.66 mmol) of bromoacetonitrile for 3.5 hours. The mixture was diluted with ethyl acetate, washed with water, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient of 0 to 4% methanol in methylene chloride to give the titled product, 1.34 gram, 82%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]#[C:14]C(O)=O)=[CH:8]2>N1C2C(=CC=CC=2)C=CC=1.O>[C:13]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH:8]=1)#[CH:14]
Reactant: COc1cccc2cc(C#CC(=O)O)ccc12
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: C#Cc1ccc2c(OC)cccc2c1

Procedure:
5-methoxynaphth-2-ylpropiolic acid (5.85) is heated at 120-124° for 5 hours in quinoline. The reaction product is diluted with water and washed thoroughly with dilute hydrochloric acid. This is followed by washing with sodium bicarbonate (10%). The material is passed through a short aluminum (H+) column, eluted with N-hexane to give a fraction free of carbonyl absorption (I.R.). Removal of solvent gives 2-ethynyl-5-methoxynaphthalene.
Reaction SMILES: [C:1]([CH:3]1[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[NH2:2][CH2:1][CH:3]1[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: N#CC1CN2CCC1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1CN2CCC1CC2

Procedure:
A solution of 3-cyanoquinuclidine (3.0g) was added to a stirred suspension of LiAlH4 (1.1g) in dry THF (250ml) and the reaction heated to reflux for 3h. On cooling the reaction, water (1ml), 2.5N NaOH solution (1.5ml) and then water (2.5ml) were added carefully and the solids removed by filtration. Evaporation of the filtrate gave the title compound, D1 (3.1g) as an oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:35])[C:4]([N:6]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:8]2([CH2:13][CH2:12][N:11]([CH:14]3[CH2:20][CH:19]4[N:21](C(OC(C)(C)C)=O)[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH2:10][CH2:9]2)[CH2:7]1)=[O:5].O1CCOCC1.Cl>CO.CCOCC>[CH:19]12[NH:21][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]([N:11]1[CH2:10][CH2:9][C:8]3([C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:6]([C:4]([N:3]([CH3:35])[CH3:2])=[O:5])[CH2:7]3)[CH2:13][CH2:12]1)[CH2:20]2
Reactant: CN(C)C(=O)N1CC2(CCN(C3CC4CCC(C3)N4C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)C(=O)N1CC2(CCN(C3CC4CCC(C3)N4)CC2)c2ccccc21
Reaction time: 8 h

Procedure:
Tert-butyl 3-(1-(dimethylcarbamoyl)spiro[indoline-3,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride 6ac (0.850 g, 1.683 mmol) was dissolved in MeOH (5 mL) followed by dioxane (40 mL) and treated with 4N HCl in dioxane (4.21 mL, 16.83 mmol). The reaction was allowed to stir overnight (complete conversion). The mixture was diluted with Et2O (150 mL) and filtered. The precipitate was washed with EtOAc (3×30 mL) and dried to provide 1′-(8-azabicyclo[3.2.1]octan-3-yl)-N,N-dimethylspiro[indoline-3,4′-piperidine]-1-carboxamide 6ad bis-hydrochloride as an off white solid (95% purity by LC/MS). This material was used for the next step without further purification. LC/MS m/z 369.0 [M+H]+ retention time 1.04 minutes (10-99% CH3CN—H2O gradient with 0.03% TFA, 5 min)
Reaction SMILES: [Li]CCCC.[CH:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1.Br[CH2:16][CH2:17][CH:18]([Br:20])[CH3:19].[NH4+].[Cl-]>C1COCC1>[Br:20][CH:18]([CH3:19])[CH2:17][CH2:16][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: CC(Br)CCBr
Reactant: CCOC(=O)C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCC(C)Br)CCC1
Temperature: -78 °C
Reaction time: 0.62 h
Yield: 41 %

Procedure:
To a 0° C. solution of DIPA (14.3 mL, 102 mmol) in THF (100 mL) was added n-BuLi (2.5M, 102 mmol). The Rx was stirred for 30-45 min then cooled to −78° C. Ethyl cyclobutane carboxylate (102 mmol, 1 equiv) was added slowly and the enolate was allowed to form for ˜30 min. At ˜78° C., above enolate was poured into 1,3-dibromobutane (2 equiv, 200 mmol) and Rx stirred at −78° C. for 1 h then warmed-up to RT. After 3 hours, NH4Cl was added and reaction extracted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated down to give 25 g of crude product. The residue was purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to provide 11 g (42% yield) of racemic ethyl 1-(3-bromobutyl)cyclobutanecarboxylate 92.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C(O)=O>[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)Nc1nc2ccc(Cl)nn2c1I
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2ccc(Cl)nn2c1-c1ccncc1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
A sealable vial was charged with N-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (74.0 mg, 220 μmol), 4-pyridylboronic acid (32.4 mg, 264 μmol), sodium carbonate (93.2 mg, 880 μmol), and dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II) (122 mg, 220 μmol). The vial was sealed with a septum cap and 1,4-dioxane (2 mL) was added under positive N2 flow followed by water (1 mL). The mixture was sparged with N2 for 10 min and heated at 80° C. for 18 h. The solution was concentrated and the residue was taken up in minimal MeOH/DMSO and purified by preparative HPLC (Gilson GX-281, Middletown, Wis.: 5-90% (0.1% TFA in CH3CN) in H2O over 15 min, Phenomenex, Zorbax 00F-4435-UO 150×30 mm, 5 micron) to afford N-(6-chloro-3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (47.0 mg, 74.3% yield) as a trifluoroacetic acid salt. LCMS (ESI positive ionization) m/z: 288.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1ccc(N)cn1
Product: CC(=O)Nc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
prepared by reaction of N-(5-amino-pyridin-2-yl)-acetamide with 4-tert-butyl-benzene-sulfonyl chloride
Reaction SMILES: [Na].N.[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH2:23])=[O:22])[CH2:16][CH2:15]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](OCC)=[O:31]>>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([NH:23][C:21]([NH:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[CH2:15][CH2:16]1)=[O:22])=[O:31]
Reactant: NC(=O)NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: CCOC(=O)c1ccccn1
Agent: N
Agent: [Na]
Product: O=C(NC(=O)c1ccccn1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.5 %

Procedure:
Sodium (0.1 g, 4.35 mmol) in liquid ammonia (100-150 cm3) was stirred until the blue colour was discharged. A bomb was charged with [1-(naphth-2-ylmethyl)piperid-4-yl]urea (0.83 g, 2.93 mmol) and the liquid ammonia solution was added. The mixture was stirred at room temperature for 2 days then the bomb was cooled to -78° C., and ethyl picolinate (0.6 g, 3.97 mmol) was added. Stirring was continued for 3 hours at room temperature then the ammonia was allowed to evaporate and the gummy residue triturated with water then ethyl acetate. The ethyl acetate suspension was filtered to give recovered [1-(naphth-2-ylmethyl)piperid-4-yl]urea (0.33 g). The filtrate was evaporated and the residue chromatographed on silica eluting with chloroform then chloroform: ethyl acetate 4:1 to give the title compound (0.37 g).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](OC)=[O:11])(=[O:4])=[O:3].[BH4-].[Li+]>O1CCCC1>[OH:11][CH2:10][C:6]1[S:7][CH:8]=[CH:9][C:5]=1[S:2]([NH2:1])(=[O:4])=[O:3]
Reactant: COC(=O)c1sccc1S(N)(=O)=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccsc1CO
Yield: 41.2 %

Procedure:
To 5.0 g of methyl 3-aminosulfonylthiophene-2-carboxylate in 200 mL of tetrahydrofuran was added 0.75 of lithium borohydride. After heating at reflux for two hours the reaction was quenched with water and acidified with concentrated hydrochloric acid. The desired product was then extracted into methylene chloride which was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 1.8 g of a yellow solid, m.p. 85°-89°.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:18][CH:19]([CH2:23][CH3:24])[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH:19]([CH2:23][CH3:24])[C:20]([NH:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][OH:10])=[O:21]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CCC(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-phenylglycinol (2.00 g, 14.6 mmol) and triethylamine (2.03 mL, 14.6 mmol) in CH2Cl2 (100 mL) at 0° C. was slowly added 2-chlorobutyryl chloride (1.66 mL, 14.6 mmol). After 30 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with CH2Cl2 (2×75 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—70:30 to 0:100, to give the title compound. MS: m/z=242 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:29]=[CH:28][C:16]3[N:17](COCC[Si](C)(C)C)[CH:18]=[N:19][C:15]=3[CH:14]=2)[C:9]1=[O:30].CO>Cl.O1CCOCC1.C(Cl)(Cl)Cl>[NH:17]1[C:16]2[CH:28]=[CH:29][C:13]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:30])=[CH:14][C:15]=2[N:19]=[CH:18]1
Reactant: Cc1ccncc1N1CCN(c2ccc3c(c2)ncn3COCC[Si](C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2ccc3[nH]cnc3c2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.4 %

Procedure:
1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-5-yl]-imidazolidin-2-one (260 mg, 0.6138 mmol) in 1,4-dioxane hydrochloride (15 mL) was taken in a reaction flask and the flask was stirred at room temperature for 12 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated under reduced pressure and the concentrate was washed with diethyl ether and hexane to afford 26 mg of the product (46.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:25])[CH3:24].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:24])[CH3:25]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(C(C)C)cc3c(=O)[nH]2)c1
Product: CC(C)c1cc2c(N3CCCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C19H20FN5O2, 369.2
Reaction SMILES: C[C:2]1[NH:3][C:4]([CH2:10][CH3:11])=[CH:5][C:6]=1[C:7]([OH:9])=[S:8].[OH-].[Na+]>C(O)C>[CH2:10]([C:4]1[NH:3][CH:2]=[C:6]([C:7]([OH:9])=[S:8])[CH:5]=1)[CH3:11]
Reactant: CCc1cc(C(O)=S)c(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C(O)=S)c[nH]1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
Methyl 5-ethylthiopyrrole-3-carboxylic acid (100 mg.) was combined with 5 ml. of ethanol and 5 ml. of 1N sodium hydroxide and heated on a steam bath in an open flask for 1 hour. The aqueous residue was cooled to room temperature and extracted with 2 ml. of ether. The aqueous phase was acidified with conc. hydrochloric acid to yield crystalline 5-ethylthiopyrrole-3-carboxylic acid (38 mg., m.p. 110°-112° C., m/e 171).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[C:14]3=[C:15]4[S:21][CH:20]=[CH:19][C:16]4=[N:17][CH:18]=[C:13]3[N:12]=[C:11]2[C@H:22]([OH:24])[CH3:23])[CH2:6][C@H:5]1[NH:25]C(=O)OCC1C=CC=CC=1)#[N:2]>[Pd].CO>[NH2:25][C@@H:5]1[CH2:6][C@@H:7]([N:10]2[C:14]3=[C:15]4[S:21][CH:20]=[CH:19][C:16]4=[N:17][CH:18]=[C:13]3[N:12]=[C:11]2[C@H:22]([OH:24])[CH3:23])[CH2:8][CH2:9][C@@H:4]1[CH2:3][C:1]#[N:2]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)[C@H](N)C1
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A mixture of benzyl ((1R,2R,5S)-2-(cyanomethyl)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)carbamate (18 mg, 0.037 mmol) and 10% palladium on carbon (24 mg) in methanol (0.27 mL) was stirred under an atmosphere of H2 (balloon) overnight. The mixture was filtered and concentrated. The crude was purified using prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3.2 mg of the desired product. LCMS calculated for C18H22N5OS (M+H)+: m/z=356.2. Found: 356.1.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](O)(=[O:27])[C:18]1[CH:26]=[CH:25][C:24]2[O:23][CH2:22][O:21][C:20]=2[CH:19]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([C:18]2[CH:26]=[CH:25][C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=2)[OH:27])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc3c(c1)OCO3)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and piperonylic acid (benzo[1,3]dioxole-5-carboxylic acid)
Reaction SMILES: C(O[K])(C)(C)C.[CH:7]12[S:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9](=O)[CH2:8]2.S([CH2:26][N+:27]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CCOCC>CC(O)(C)C.COCCOC.COCCOC>[CH:7]12[S:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]([C:26]#[N:27])[CH2:8]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CC2CCC(C1)S2
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: N#CC1CC2CCC(C1)S2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-BuOK (2.41 g, 21.52 mmol) in t-BuOH/DME 1:2 (24 ml) was added at 0° C. to a solution of 8-thiabicyclo[3.2.1]octan-3-one (1.53 g, 10.75 mmol) and tosylmethyl isocyanide (2.3 g, 11.83 mmol) in DME (20 ml). The solution was stirred for 3 hours at room temperature. After addition of ether, the mixture was washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated. After purification by chromatography on silica gel (hexane/AcOEt 85/15), 8-thiabicyclo[3.2.1]octane-3-carbonitrile was obtained as a colorless oil (1.03 g, 63%).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([CH2:33][CH3:34])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1.[CH2:35]([O:42][CH:43]1[CH:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:46]([CH2:65][O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[O:45][C:44]1=[O:74])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>C1COCC1>[CH2:35]([O:42][C@@H:43]1[C@H:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:47]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[C@@H:46]([CH2:65][O:66][CH2:67][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[O:45][C:44]1([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([CH2:33][CH3:34])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1)[OH:74])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: CCc1ccc2sc(Cc3cc(Br)c4ccccc4c3)cc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc2sc(Cc3cc(C4(O)O[C@H](COCc5ccccc5)[C@H](OCc5ccccc5)[C@@H](OCc5ccccc5)[C@H]4OCc4ccccc4)c4ccccc4c3)cc2c1
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 0.83 ml, 1.33 mmol) was added dropwise to a solution of 2-(4-bromonaphtalen-2-ylmethyl)-5-ethylbenzo-[b]thiophene (460 mg, 1.21 mmol) in THF (15 ml) at −78° C. The reaction mixture was stirred at the same temperature for five minutes and to this solution, a solution of 3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydro-pyran-2-one (844 mg, 1.57 mmol) in THF (5 ml) was added dropwise. The reaction solution was stirred at −78° C. for five minutes and a saturated ammonium chloride aqueous solution was added to stop the reaction. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:9)] to obtain the title compound (1.06 mg, 100%).