Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:17][C:18]#[N:19])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]1[C:29]2[C:28]([N:30]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH3:36])[CH2:31]3)=[N:27][CH:26]=[N:25][C:24]=2[NH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[C:29]4[C:21]([CH3:20])=[CH:22][NH:23][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:31][C@@H:32]2[CH3:36])=[N:17][C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Reactant: N#CN=C(Nc1cccc(Cl)c1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(Cl)c4)[C@@H](C)C3)c12
Temperature: 85 °C
Yield: 46.5 %

Procedure:
The cyanocarbamimidate from step A (0.47 g, 1.7 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine from Example 1, step B (0.40 g, 1.7 mmol), and N,N-diisopropylethylamine (1 ml) were added to acetonitrile (10 ml). The mixture was heated at 85° C. in a sealed pressure tube for 4 hours. The solvent was evaporated, and the residue was purified by flash chromatography (80 g SiO2, 0-5% MeOH:CH2Cl2, 50 min) to give (S)—N-(3-chlorophenyl)-N′-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (0.32 g, 0.79 mmol, 46%).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].Cl.[NH2:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)C(C)CSC(C)=O

Procedure:
3-Acetylthio-2-methylpropanoyl chloride (3.78 ml., 25 mmole) is added dropwise over six minutes to a cold (-5°), stirred suspension of (L)-methionine, methyl ester, hydrochloride salt (4.99, 25 mmole) and triethylamine (13.94 g.) in methylene chloride (100 ml.). The mixture is stirred in the cold for three hours and then diluted with methylene chloride (100 ml.). The resulting yellow solution is washed sequentially with 10% aqueous HCl (70 ml.), saturated sodium bicarbonate (70 ml.) and brine (100 ml.), dried over sodium sulfate, and concentrated in vacuo to give (±)-N-[3-(acetylthio)-2-methyl-1-oxopropyl]-L-methionine, methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][NH2:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][NH:31][C:39](=[O:41])[CH3:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,5S)-2-aminomethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (200 mg), and Et3N (77 μL, 0.55 mmol) in CH2Cl2 (3 mL) was added under nitrogen atmosphere at 0° C. acetyl chloride (39 μL, 0.55 mmol) and the mixture was stirred at 0° C. for 1 h. CH2Cl2 and 1N aqueous HCl were added, the layers were separated and the aqueous one back-extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 0:100) to give the title compound. MS (LC/MS): 480.1 [M+H]+; tR (HPLC conditions b): 4.69 min.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15]1.[OH-].[Li+]>C1COCC1.O>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([N:14]2[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15]2)=[C:4]([CH:9]=1)[C:3]([OH:20])=[O:2])(=[O:11])=[O:12]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1-n1cc(C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnn(-c2ccc(S(C)(=O)=O)cc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.08 mmol 5-Methanesulfonyl-2-(4-methyl-pyrazol-1-yl)-benzoic acid methyl ester in 2.2 ml THF and 2.2 ml water was added 3.12 mmol lithium hydroxide and the reaction mixture was stirred at RT for 2 hours. After such time the solvent was removed in vacuo, the residue was taken in water and acidified by addition of 3N HCl to yield after filtration the title compound as a white solid (88%). MS (m/e): 279.1 ([M−H], 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]([F:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]([F:35])([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(F)(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 28.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (95 mg, 0.19 mmol) obtained in step 4 and ethanesulfonamide (100 mg, 0.95 mmol), the title compound (32 mg, 29%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].Cl[Mg][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].O1CCCC1.Cl.O>O1CCCC1>[CH3:17][C:18]([CH3:21])([CH3:20])[CH2:19][CH:7]([C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:3][C:2]=1[CH3:1])[OH:8]
Reactant: Cc1oc(-c2ccccc2)cc1C=O
Reactant: CC(C)(C)C[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)cc1C(O)CC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 2-methyl-5-phenylfuran-3-carbaldehyde (1.1 g) in tetrahydrofuran (20 mL) was added dropwise 1N chloro(2,2-dimethylpropyl)magnesium-tetrahydrofuran solution (9 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give the title compound (1.1 g, 70%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9](O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[CH2:15][CH2:16][OH:17].CN(C)C=O>O>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([CH2:15][CH2:16][OH:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: OCCBr
Reactant: Oc1c(Br)cc(Br)c2cccnc12
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1c(Br)cc(Br)c2cccnc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A solution of 3.79 g of 5,7-dibromo-8-hydroxyquinoline (12.5 mmol) and 975 mL of 2-bromoethanol (13.75 mmol) in 20 mL of dry dimethylformamide containing 5.18 g anhydrous potassium carbonate (37.5 mmol) was placed under argon atmosphere and heated at 60° C. with vigorous magnetic stirring. After 4 hr a further 220 μL of 2-bromoethanol was added and stirring continued at 60° overnight. After 22 hr another 440 μL of 2-bromoethanol was added. After 4 days the mixture was poured into 150 mL of water while stirring. The precipitated product was collected by filtration, washed with 50 mL of 0.5 M aqueous potassium carbonate, plain water and air dried. The solid was washed through the funnel by dissolving in dichloromethane, and the solvent was removed to yield 3.18 g of 5,7-dibromo-8-(2-hydroxyethyl)quinoline. After recrystallization from methanol/water containing a little triethylamine, the melting point was 128–131° C.
Reaction SMILES: N1CCOCC1.BrC1OC(C=O)=CC=1.[N:15]1([C:21]2[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:33][C:34]#[N:35]>>[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[C:33](=[CH:26]/[C:24]2[O:25][C:21]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:22][CH:23]=2)/[C:34]#[N:35])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: O=Cc1ccc(N2CCOCC2)o1
Reactant: COc1ccc(CC#N)cc1OC
Agent: O=Cc1ccc(Br)o1
Solvent: C1COCCN1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCOCC3)o2)cc1OC
Yield: 39.3 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from morpholine (523 mg) was introduced into 5-bromo-2-furaldehyde (350 mg), to thereby yield 5-morpholin-4-yl-furan-2-carbaldehyde (yield: 138 mg, 38%). The produced 5-morpholin-4-yl-furan-2-carbaldehyde (137 mg) was condensed with 3,4-dimethoxybenzyl cyanide (135 mg) through Method A (production step 2), to thereby yield the target product (yield: 102 mg, 40%).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[O:26])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCn1c2ccccc2c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCn1c2ccccc2c2cc(C(=O)c3ccccc3C(=O)O)ccc21

Procedure:
To a mixture of 8.17 g (0.05 mole) of N-ethylcarbazole and 3.7 g (0.025 mole) of phthalic anhydride in 112 g of chlorobenzene, 6.65 g (0.05 mole) of aluminum chloride was added in small increments at ambient temperature after which the mixture was warmed in the range of 50°-70° C. for two hours. The reaction mixture was poured onto ice and rendered acidic by the addition of 10 percent hydrochloric acid. The chlorobenzene layer was separated and steam-distilled to remove the chlorobenzene. The residue was extracted with 10 percent aqueous sodium hydroxide, filtered to remove the insolubles and then acidified with dilute hydrochloric acid. The solid which separated was collected by filtration, washed with water and dried to obtain 2-[(9-ethyl-3-carbazolyl)carbonyl]benzoic acid (Formula VII: R°=R1 =R2 =R3 =H; R8 =CH2CH3) melting over the range 120°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:20]([C:21]([OH:23])=O)=[C:19]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:18][N:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.Cl.[CH3:33][O:34][C:35](=[O:41])[C@@H:36]([NH2:40])[CH2:37][O:38][CH3:39].[K+].[Br-]>>[CH3:33][O:34][C:35](=[O:41])[C@@H:36]([NH:40][C:21]([C:20]1[C:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:31]=[CH:30][C:5]=4[N:6]=3)=[CH:15][CH:14]=2)=[N:17][O:18][C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:23])[CH2:37][O:38][CH3:39]
Reactant: COC[C@H](N)C(=O)OC
Reactant: O=C(O)c1c(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)noc1-c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC[C@H](NC(=O)c1c(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)noc1-c1ccccc1)C(=O)OC
Yield: 69 %

Procedure:
The title compound was prepared from 3-[4-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-5-phenyl-isoxazole-4-carboxylic acid and (S)-2-amino-3-methoxy-propionic acid methyl ester hydrochloride as set forth in Example 5 and was obtained in 69% yield. Mass (ES+): 547 (M++1); IR (KBr): 3342, 3270, 1718, 1648, 1605, 1542; 1H NMR (DMSO-d6) δ: 3.23 (s, 3H), 3.61-3.68 (br, 5H), 4.79 (m, 1H), 7.16 (m, 1H), 7.53-7.58 (m, 4H), 7.80-7.87 (m, 7H), 9.53 (d, 1H), 10.73 (s, 1H, NH).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[C-:10]#[N:11].[Na+]>CO.CCOC(C)=O>[Cl:9][C:4]1[C:3]([CH2:2][C:10]#[N:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: [C-]#N
Reactant: Clc1ncccc1CBr
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CCc1cccnc1Cl
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
In a 250 mL round bottom flask was dissolved 3-(bromomethyl)-2-chloropyridine (7.2 g, 35 mmol) in MeOH (70 mL). To the solution was added sodium cyanide (3.4 g, 70 mmol), then attached a reflux condenser, stirred the mixture at 80° C., while monitoring the reaction by LCMS. After about 1.5 h, the reaction was cooled to RT, concentrated, diluted with EtOAc, upon which a white solid crashed out. The solids were filtered and rinsed with EtOAc. The organic filtrate was concentrated to yield a crude reddish brown solid. The solid was dissolved in EtOAc, and purified by silica gel chromatography eluting with 40-70% EtOAc/Hexanes. The product fractions were concentrated to yield 2-(2-chloropyridin-3-yl)acetonitrile as an off-white solid. MS m/z=153 [M+1]+. Calc'd for C7H5ClN2: 152.58.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CC(=O)O
Product: Cc1nc2cc(Br)cnc2[nH]1
Yield: 82 %

Procedure:
To 5.06 g of 5-bromo-2,3-diaminopyridine 46 (Ryabukhin et al (2006) Synthesis 21:3715-3726; Oguchi et al (2000) J. Med. Chem. 43(16):3052-3066; Seki et al (1995) J. Hetero. Chem. 32(3):1071-73; Fray et al (1995) J. Med. Chem. 38(18):3524-35) was added 50 mL acetic acid under N2 and the reaction was heated to reflux overnight. Complete reaction was confirmed by LCMS. The solution was concentrated in vacuo and purified by flash chromatography (DCM/MeOH) to give 4.68 g of 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine 51 (82% yield), which may also be prepared by the methods of Cee et al (2007) J. Med. Chem. 50(4):627-40; Itoh et al (1982) J. Hetero. Chem. 19(3):513-17. 6-Bromo-2-methyl-3H-imidazo[4,5-b]pyridine (4.68 g) in 150 mL THF was added to 0.63 g (1.1 eq) NaH in 10 mL THF under N2 at −78° C. The reaction was stirred at −78° C. for 30 minutes followed by the addition of 3.86 g of SEM-Cl (1.05 eq) and allowed to warm up to room temperature. The reaction was stirred at room temperature 4.5 hours and complete reaction was confirmed by LCMS. The reaction was quenched with water followed by the addition of NaCl (not saturated) and the two products extracted with EtOAc and concentrated in vacuo. The two regioisomers were separated by flash chromatography (EtOAc/Hexanes) to give 2.84 g 6-bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 and 1.94 g 6-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine 53 (63% overall yield). 6-Bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 (2.08 g) was dissolved in 50 mL toluene followed by the addition of 2.32 g (1.5 eq) of bis(pinacolato)diboron, 0.24 g (0.05 eq) of PdCl2(dppf), and 1.79 g (3.0 eq) of KOAc. The reaction mixture was heated to 95° C. under N2 and let stir overnight. Complete reaction confirmed by LCMS. The mixture was cooled to room temperature, rotovapped and purified by flash chromatography (EtOAc/Hexanes) to give 1.83 g of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 54 (77% yield). MS (Q1) 390.2 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:23])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(=O)=O.CC(C)=O>C1COCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:23])[C:14]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccc(Cl)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of methyl 5-bromo-2-(2-(4-chlorophenoxy)acetamido)benzoate (5.15 g, 12.9 mmol, Intermediate 7: step a) in THF (140 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5 M in toluene, 76.7 mL, 38.4 mmol) over 4 minutes, and the mixture was stirred for 5 minutes. The dry-ice/acetone bath was replaced an with an ice-water bath and the reaction was stirred for 1.5 hours. The reaction was then quenched with water and ethyl acetate was added. The organic layer was removed and the aqueous layer was acidified with 2 N HCl (kept pH above 2). An off-white precipitate formed which was filtered and the solid was dried overnight in the air to yield the title compound.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.Cl.[NH2:13][OH:14].N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=[N:13][OH:14])[CH2:2]1)[CH2:8]2
Reactant: NO
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1C2CC3CC1CN(C3)C2

Procedure:
A solution of 1-aza-adamantan-4-one (1.1 g), hydroxylamine hydrochloride (0.7 g) and pyridine (0.5 ml) in ethanol (30 ml) was heated under reflux for 1 h. The solution was then treated with saturated K2CO3 solution (30 ml), evaporated to half its volume and extracted with CH2Cl2 (4×50 ml). The combined extracts were dried (K2CO3) and evaporated in vacuo to give D.1 (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:7][C:6]4[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:10]([F:13])([F:12])[F:11])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: FC(F)(F)c1ccc(Cl)cc1CCl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 5-chloro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (48% yield). 1H NMR (300 MHz, CDCl3) δ 7.96-8.05, 7.87, 7.58, 7.34, 6.97, 3.80, 3.70, 3.56, 2.64, 1.53, 1.51, 0.70-0.83, 0.43-0.51, 0.07-0.13. MS (ES+) m/z 468 (M+1).
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Reactant: O=C(Cl)c1ccccc1
Agent: I
Solvent: c1ccncc1
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a mixture of Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (100 mg; 0.32 mmol) in pyridine (2 mL) was added benzoyl chloride (0.12 mL; 0.96 mmol) dropwise. The mixture was then agitated at 80° C. in a sealed tube overnight. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The residue was taken up into ethyl acetate and the extract allowed to stir with 2M sodium carbonate solution for 2 hours at room temperature. The organic layer was then washed with brine solution, dried over sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (eluent: 10% ethyl acetate/hexanes to 40% ethyl acetate gradient) to provide 53 mg of N-(8H-Indeno[1,2-d]thiazol-2-yl)-benzamide 2. EI-HRMS m/e calcd for C17H12N2OS 292.0670, found 292.0666.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:23][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[CH:18][CH:17]=[CH:16]3)C1C=CC=CC=1.Cl.[C:25]1(C)C=CC=CC=1>>[CH3:25][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][C@H:10]([CH2:9][OH:8])[O:23][C:14]3=2)[N:19]=1
Reactant: c1ccc(COCC2COc3ccc4ncccc4c3O2)cc1
Reactant: Cc1ccccc1
Agent: Cl
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CO)O3
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A mixture of crude (2S)-2[(benzyloxy)methyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoline product mixture (57.6 g, 0.179 mol) from example 7 in toluene (300 mL) was mixed with 20% HCl (436 g, 3.59 mol) and heated at 80° C. After 30 min, the reaction mixture was cooled to room temperature. The two layers were separated. A 30% NH4OH solution (400 mL) was added to the aqueous layer at 10–20° C. to pH 10. This was stirred for 30 min, the solid was filtered, washed with water and recrystallized from CH3OH (200 mL) to give 25.7 g (61.9%) of the title alcohol as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=1.C([O-])([O-])=O.[Ca+2].O.[C:18](Cl)(Cl)=[S:19]>C(Cl)Cl>[CH3:8][C:6]1[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=[C:2]([N:1]=[C:18]=[S:19])[N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(N)nc(C)c1C#N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(N=C=S)nc(C)c1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A suspension of 6-amino-3-cyano-2,4-dimethylpyridine (0.1 g, 0.68 mmol) in CH2Cl2 (1 mL) was added to a vigorously stirred mixture of CaCO3 (0.41 g, 4.11 mmol) in a 1:2 water:CH2Cl2 mixture (9 mL total) at room temp. The reaction mixture was cooled to 0° C. and thiophosgene (0.09 g, 0.78 mmol) was added dropwise. The resulting mixture was allowed to warm to room temp and was stirred overnight. The resulting aqueous layer was back-extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with water (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 10% EtOAc/hex) to give 2,4-dimethyl-3-cyano-6-pyridyl isothiocyanate (0.12 g, 91%): CI-MS m/z 190 ((M+H)+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][CH:12]([OH:14])[CH3:13].[NH2:15][C:16]1[CH:23]=[C:22](F)[C:19]([C:20]#[N:21])=[CH:18][N:17]=1>C1COCC1>[NH2:15][C:16]1[CH:23]=[C:22]([O:14][CH:12]([CH3:13])[CH3:11])[C:19]([C:20]#[N:21])=[CH:18][N:17]=1
Reactant: CC(C)O
Reactant: N#Cc1cnc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(N)ncc1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of KHMDS (87 g, 438 mmol) was added portionwise to a solution of propan-2-ol (26.3 g, 438 mmol) in THF (250 ml) at room temperature. After 15 min a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 30 g, 219 mmol) in THF (200 ml) was added and the reaction mixture stirred for 18 h at room temperature. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc, extracted with EtOAc (2×), the combined EtOAc layers were dried over Na2SO4 and evaporated. The residue was triturated with Et2O and the product obtained by filtration as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 6.82 (s, 2H), 6.07 (s, 1H), 4.64 (septet, 1H), 1.31 (d, 6H). (UPLC-MS 7) tR 0.61; ESI-MS 178.1 [M+H]+.