Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:2]1=2.O.[OH-].[Li+]>CO.O>[C:18]([O:17][C:15]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:2]1=2)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1cnc2c(c1)N(C(=O)OC(C)(C)C)CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2ncc(C(=O)O)cc21
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a suspension of 1-tert-butyl 7-methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1,7-dicarboxylate (1.25 g, 4.25 mmol) in methanol (20 mL) and water (5 mL) was added lithium hydroxide monohydrate (1.27 g, 30.3 mmol). The reaction was warmed to 40° C. and stirred at that temperature for 18 h. The reaction mixture was concentrated in vacuo to provide 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid. The yield was assumed to be 100% for calculation purposes in subsequent reactions. LCMS (+ESI) m/z=281.1 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:20]>C(Cl)Cl.O1CCOCC1>[ClH:20].[Br:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCCCBr)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: BrCCCCOC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.47 g (7.35 mmol) 4-(4-Bromo-butoxy)-piperidin-1-carboxylic acid tert-butyl ester in 10 ml of CH2Cl2 was added 20 ml of 4N HCl in dioxane. The reaction-mixture was stirred for 2 h at RT and then concentrated under reduced pressure. The crude residue was suspended several times with Et2O and then dried in vacuo to yield 1.78 g (quantitative) of 4-(4-Brom-butoxy)-piperidine hydrogen chloride, MS: 236 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21]([OH:23])=O)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2].[CH3:34][NH:35][CH3:36]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21]([N:35]([CH3:36])[CH3:34])=[O:23])=[O:17])[CH2:14][CH2:15]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)O)ccc3N3CCOCC3)CC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)N(C)C)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step2 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-morpholin-4-yl-benzoic acid and dimethylamine (44%, yellow solid, MS (m/e): 483.2 (M+H, 100%)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([SH:9])[CH3:8].Cl[C:11]1[C:20]([NH:21][C:22](=[O:29])[CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][C:18]2[C:13](=[CH:14][C:15]([C:30]([F:33])([F:32])[F:31])=[CH:16][CH:17]=2)[N:12]=1.CCCCCC.CC(=O)OCC>CN(C=O)C.O>[CH2:7]([S:9][C:11]1[C:20]([NH:21][C:22](=[O:29])[CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][C:18]2[C:13](=[CH:14][C:15]([C:30]([F:31])([F:32])[F:33])=[CH:16][CH:17]=2)[N:12]=1)[CH3:8]
Reactant: CCS
Reactant: O=C(Cc1cccs1)Nc1cc2ccc(C(F)(F)F)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCSc1nc2cc(C(F)(F)F)ccc2cc1NC(=O)Cc1cccs1
Temperature: 60 °C
Yield: 74.1 %

Procedure:
331 mg (2.4 mmol) of K2CO3 and 40 mg (1.6 mmol) of ethanethiol were added to a solution of 300 mg (0.81 mmol) of N-(2-chloro-7-(trifluoromethyl)quinolin-3-yl)-2-(thiophen-2-yl)acetamide in DMF (6 ml), and the mixture was heated for 16 h at 60° C. It was then diluted with water and extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 9:1) of the residue yielded 242 mg (0.6 mmol, 74%) of N-[2-ethylsulfanyl-7-(trifluoromethyl)-quinolin-3-yl]-2-thiophen-2-yl-acetamide. MS: m/z 397.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19]CC)=O)=[CH:10][CH:9]=1.C(O)(C)C.CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[O:22][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=C1CCC(c2ccc(-c3ccccc3F)cc2)O1
Yield: 78 %

Procedure:
A mixture of 9 gm (0.03 mol) of ethyl 4-(2'-fluoro-4-biphenylyl)-4-oxo-butyrate, 150 ml of absolute isopropanol and 6.2 gm (0.03 mol) of freshly distilled aluminum isopropylate was refluxed on a boiling water bath, while condensing the vapors in a descending condenser, until no more acetone was detectable in the distillate. After removing the solvent in vacuo, the residue was covered with ether, the mixture was acidified with dilute hydrochloric acid, and the ethereal phase was separated, washed with sodium bicarbonate and water. After distilling off the solvent, the solid residue was recrystallized from cyclohexane, to yield 6 gm (78% of theory) of colorless γ-(2'-fluoro-4-biphenylyl)-γ-butyrolactone, m.p. 74°-75° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O.O.[NH2:23][NH2:24]>CN(C1C=CN=CC=1)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=3)[NH:24][N:23]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)cc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Yield: 39.6 %

Procedure:
Prepared according to Method D Step A from (2-Fluoro-3-trifluoromethylphenyl)-(4-methoxyphenyl)-methanone (3.6 g, 14.7 mmol), hydrazine hydrate (4.3 mL, 140 mmol) and DMAP (1.8 g, 14.7 mmol) to give the product (1.7 g) as a yellow solid.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)=[CH:3][CH:2]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[S:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[S:41][C:42]1[CH:43]=[C:44]([NH:45][C:13]([NH:12][C:11]2[N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=3)[N:8]=[C:9]([C:22]([F:23])([F:24])[F:25])[CH:10]=2)=[O:21])[CH:46]=[CH:47][CH:48]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cc1ccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(C)cc4)c3)c2cc1OC
Yield: 83 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 172B (0.145 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.192 g, 83%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.74 (s, 1H), 8.69 (d, 1H), 7.78 (s, 1H), 7.45 (m, 6H), 7.35 (s, 1H), 7.33 (s, 1H), 7.25 (d, 1H), 6.85 (s, 1H), 3.99 (s, 6H), 2.41 (s, 3H); LC-MS (ESI) m/z 581 (M+H)+.
Reaction SMILES: CC[CH:3]1[C:23]2(CC)[C:24]3=[N:25][C:4]1=[CH:5][C:6]1[NH:10][C:9]([CH:11]=[C:12]4[NH:39][C:15](=[CH:16][C:17]5[C:34](CC)=[C:33](CC)[C:19](=[C:20]3C=C2C(OCC)=O)[N:18]=5)[C:14](CC)=[C:13]4CC)=[C:8](CC)[C:7]=1CC>ClCCl>[C:6]12[CH:5]=[C:4]3[N:25]=[C:24]([CH:23]=[CH:3]3)[CH:20]=[C:19]3[NH:18][C:17]([CH:34]=[CH:33]3)=[CH:16][C:15]3=[N:39][C:12]([CH:13]=[CH:14]3)=[CH:11][C:9]([NH:10]1)=[CH:8][CH:7]=2
Reactant: CCOC(=O)C1=Cc2c3nc(cc4[nH]c(cc5[nH]c(cc6nc2C1(CC)C6CC)c(CC)c5CC)c(CC)c4CC)C(CC)=C3CC
Solvent: ClCCl
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
A 50 mg portion of Purpurin NT2 was dissolved in 20 ml dichloromethane, and the resulting solution was allowed to stand for a total of 16 hours in sunlight, in contact with air, and under ambient conditions (temperature about 22°). The dichloromethane was then removed by evaporation, leaving 50 mg porphyrin derivative (hereafter "Porphyrin NT2") which was found by nuclear magnetic resonance to have the formula of FIG. 9 of the attached drawings where R1 through R8 are ethyl, R10 through R12 are hydrogen, and R13 is CH2CH3. The production of Purpurin NT2 is described in Example 1 of PCT/US86/02824; it has the formula of FIG. 5 of the drawings of that application where R1 through R8 are ethyl, R9 is CO2CH2CH3, and R10 through R13 are hydrogen.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Si:10]([O:9][CH2:8][C:4]1[N:3]=[C:2]([O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:7]=[CH:6][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(CO[Si](C)(C)C(C)(C)C)n2)CC1
Temperature: 100 °C

Procedure:
2-Bromo-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (2.7 g, 7.51 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.5 g, 7.51 mmol), palladium(II) acetate (0.034 g, 0.15 mmol), biphenyl-2-yl(di-tert-butyl)phosphine (0.056 g, 0.19 mmol) and cesium carbonate (4.9 g, 15.0 mmol) were mixed in a 40 mL vial and dry toluene (25 ml) was added. The vial was then briefly evacuated and backfilled with N2 five times, and the reaction vessel was heated at 100° C. under N2 atmosphere for 24 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with toluene (100 mL), washed with water, the organics dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography using a gradient with toluene:EtOAc (98:2-80:20), gave the product as an oil. Yield: 1.1 g (33%). 1H NMR (400 MHz, CDCl3) δ 7.44 (t, 1H, J=7.82 Hz), 6.89 (d, 1H, J=7.30 Hz), 6.43 (d, 1H, J=8.34 Hz), 5.04-5.11 (m, 1H), 4.56 (s, 2H), 3.58-3.68 (m, 2H), 3.12-3.21 (m, 2H), 1.78-1.87 (m, 2H), 1.53-1.64 (m, 2H), 1.35 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H). MS (ESI+) 423.24 (M+1H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.O[C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>>[CH2:32]([O:31][C:29](=[O:30])[C:28]1[CH:34]=[CH:35][C:25]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=3[O:20][CH:21]([CH3:23])[CH3:22])[CH2:6][CH2:7]2)=[CH:26][CH:27]=1)[CH3:33]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)cc1
Yield: 28 %

Procedure:
Prepared in analogy to Example 4 from (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 3(a)) and ethyl 4-hydroxybenzoate. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 28%). MS (m/e): 490.5 (M+H+, 100%).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1(Cl)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:14]([O:19][OH:20])([CH2:17][CH3:18])([CH3:16])[CH3:15].[OH-].[K+].C(N=NC1(O)CCCCC1)(C)(C)C>>[C:1]([N:5]=[N:6][C:7]1([O:20][O:19][C:14]([CH2:17][CH3:18])([CH3:16])[CH3:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)OO
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Agent: CC(C)(C)N=NC1(O)CCCCC1
Agent: [K+]
Agent: [OH-]
Product: CCC(C)(C)OOC1(N=NC(C)(C)C)CCCCC1

Procedure:
The 1-t-butylazo-1-(t-amylperoxy)cyclohexane was prepared in 85% crude yield from 7.5 grams (.037 moles) of 1-t-butylazo-1-chlorocyclohexane, 6.0 grams (.052 moles) of 90% t-amyl hydroperoxide and 9.1 grams (.0407 moles) of 25% potassium hydroxide solution. The procedure was the same as that described in Example XX. The infrared spectrum of the product indicated there was a small amount of 1-t-butylazo-1-hydroxycyclohexane present in the product.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C@@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1>[Pd].C(O)C>[CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C@@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1
Reactant: CC(C)(C)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)CCc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Reaction time: 12 h

Procedure:
(R)-2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (400 mg, 0.974 mmol) and palladium on carbon (104 mg, 0.974 mmol) were combined in 20 ml of ethanol and stirred under an atmosphere of hydrogen for 12 hours. The solution is filtered thru celite and concentrated. The product is purified via silica gel column chromatography (RediSep 80 g column) using 0-10% methanol in ethyl acetate to afford (R)-2′-(3,3-dimethylbutyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white crystalline solid. Found MS: MH+=415.2.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[H-].[Na+].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][C:32]=1[N+:39]([O-:41])=[O:40]>CN(C=O)C>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[CH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:33][C:32]=1[N+:39]([O-:41])=[O:40]
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C=Cc2cccnc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Triphenylpyridin-3-ylmethylphosphonium chloride (1.95 g) was added into an ice-cooled DMF suspension (40 ml) containing sodium hydride (60% in oil) (0.26 g), followed by 30 minutes of stirring at room temperature. The reaction solution was cooled to 0° C. and 4-chloro-3-nitrobenzaldehyde (1.04 g) was added portionwise thereto, followed by 2 hours of stirring at room temperature. To the residue formed by evaporating the reaction solution under reduced pressure was poured an appropriate amount of purified water, followed by extraction with ethyl acetate. Thereafter, the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by solvent evaporation was purified by silica gel column chromatography to obtain 3-[2-(4-chloro-3-nitrophenyl)vinyl]pyridine (0.86 g) from the fractions eluted with ethyl acetate-hexane (2:1 (v/v)).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH:26][CH3:27])[CH:20]=1>CN(C=O)C>[NH2:25][C:23]1[N:24]=[C:19]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[C:6]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7]2)[CH:20]=[C:21]([NH:26][CH3:27])[N:22]=1
Reactant: CN(C)C(=O)c1n[nH]c2cc(I)ccc12
Reactant: CNc1cc(Cl)nc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(-n2nc(C(=O)N(C)C)c3ccc(I)cc32)nc(N)n1
Temperature: 180 °C

Procedure:
To a suspension of 6-iodo-N,N-dimethyl-1H-indazole-3-carboxamide (100 mg, 0.32 mmol) at 0° C. in DMF (3 mL) was added sodium hydride (19 mg of a 60% dispersion in mineral oil, 0.47 mmol). The reaction mixture was allowed to warm to RT over 15 minutes before the addition of 6-chloro-4-N-methylpyrimidine-2,4-diamine (75 mg, 0.47 mmol). The reaction mixture was then heated at 180° C. for 2 hr. The reaction mixture was allowed to cool to RT. The mixture was cooled to 0° C. and quenched by addition of water (1 mL) and the volatiles evaporated in vacuo. The mixture was diluted with sat ammonium chloride (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. Purification of the residue by column chromatography (Biotage, 55-100% ethyl acetate: heptanes) gave the title compound: 1H NMR (500 MHz, DMSO) delta 2.78 (3H, s), 3.08 (3H, s), 3.42 (3H, s), 6.24 (1H, s), 6.48 (2H, s), 7.08 (1H, s), 7.64 (1H, m), 7.79 (1H, m), 9.40 (1H, s); LC-MS: m/z=+438.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C@:12]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[S:11](=[O:38])(=[O:37])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([C:17]2[S:16][C:15]([C@:12]3([CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[S:11](=[O:38])(=[O:37])[CH2:10][CH2:9][NH:8][CH2:14][CH2:13]3)=[CH:19][CH:18]=2)=[CH:25][CH:24]=1)[CH2:27][CH3:28]
Reactant: CCCc1ccc(-c2ccc([C@@]3(CC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CCS3(=O)=O)s2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc([C@@]3(CC(=O)OC(C)(C)C)CCNCCS3(=O)=O)s2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 104.5 %

Procedure:
To a solution of t-butyl 2-[(S)-4-t-butoxycarbonyl-7-(5-(4-propylphenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (10.4 g) in tetrahydrofuran (120 ml) was added conc. hydrochloric acid (30 ml) in tetrahydrofuran (30 ml) under ice-water cooling and the mixture was stirred at ambient temperature for 15 hours. The mixture was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give t-butyl 2-[(S)-7-(5-(4-propylphenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (8.94 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C:23]([O:32][CH3:33])(=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[C:23]([O:32][CH3:33])=[O:31])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: COC(=O)c1ccccc1O
Product: CCN1c2ncc(COc3ccccc3C(=O)OC)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 57 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 155°-156° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and methyl salicylate. The yield was 57% of theory.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH3:20])=[C:11]([C:21]([NH:23][C@H:24]3[CH2:29][CH2:28]C[CH2:26][C@@H:25]3[OH:30])=[O:22])[CH:10]=2)=[CH:4][CH:3]=1.N[C@H]1CCCC[C@@H]1[OH:38]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH3:20])=[C:11]([C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][O:38][CH2:26][C@@H:25]3[OH:30])=[O:22])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccc(Cl)nc2)c2ccccc12
Reactant: N[C@H]1CCCC[C@@H]1O
Product: COc1c(C(=O)N[C@H]2CCOC[C@@H]2O)cc(Cc2ccc(Cl)nc2)c2ccccc12

Procedure:
The title compound was prepared by the procedure described for the synthesis of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide in Example 3, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (1S,2S)-2-aminocyclohexanol. The resultant solid gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 426.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.24-8.19 (m, 2H), 7.99 (s, 1H), 7.87-7.84 (m, 1H), 7.62-7.55 (m, 2H), 7.39-7.36 (m, 1H), 7.17 (d, J=8.2 Hz, 1H), 4.38 (s, 2H), 4.15-4.10 (m, 2H), 4.09-4.00 (m, 1H), 4.03 (s, 3H), 3.70-3.63 (m, 1H), 3.54-3.47 (m, 1H), 3.28-3.23 (m, 1H), 2.12-2.04 (m, 1H), 1.84-1.74 (m, 1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available (25)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:3]([I:15])=[C:4]([NH:8]C(=O)C(C)(C)C)[CH:5]=[N:6][CH:7]=1.Cl>>[F:1][C:2]1[C:3]([I:15])=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cncc(F)c1I
Agent: Cl
Product: Nc1cncc(F)c1I
Yield: 82.5 %

Procedure:
N-(5-Fluoro-4-iodopyridin-3-yl)-2,2-dimethylpropanamide (8.46 g, 26.3 mmol) was heated at reflux in aqueous 3M HCl for 2 hours. The reaction was carefully quenched with aqueous sodium hydroxide (3M) until basic and the mixture was extracted with dichloromethane (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford the title compound (5.16 g, 21.7 mmol, 83% yield) as an off white solid, MS (ESI): m/z=239.18 (MH+), 90% pure by LCMS.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]3[CH2:11][NH:10][C:9](=[O:22])[C:8]=2[CH:23]=1.[CH3:24]I.O>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]3[CH2:11][N:10]([CH3:24])[C:9](=[O:22])[C:8]=2[CH:23]=1
Reactant: CI
Reactant: CCOC(=O)c1ncn2c1CNC(=O)c1cc(F)ccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.1 g (2 mmol) of sodium hydride (55 percent oil dispersion) are suspended in 10 ml of dry dimethylformamide and treated with 0.5 g (1.7 mmol) of ethyl 8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate. After completion of the gas evolution, 0.13 ml (2 mmol) of methyl iodide is added and the mixture is stirred at room temperature for 2 hours. The mixture is poured into ca 60 ml of water and extracted three times with 30 ml of chloroform each time. The combined chloroform extracts are washed with ca 30 ml of water, dried over magnesium sulphate and evaporated. After recrystallisation from ethyl acetate, there is obtained ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 196°-197° C.