Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH3:8][O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].CI>C1COCC1>[CH3:8][O:9][C:10]([C:12]1([CH3:1])[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)=[O:11]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
137 mL Diisopropylamine in 3390 mL THF was cooled to 0° C. and 360 mL n-buthyllithium was added dropwise under nitrogen. The reaction was cooled to −78° C. and a solution of 180 mL piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester in 1800 mL THF was added dropwise over 1 h. The reaction was stirred at −78° C. for 2 h and then 168 mL methyliodide in 300 mL THF was added in one portion. The mixture was stirred 2 h at −78° C. and then allowed to warm to RT. The reaction was quenched with saturated aqueous sodium sulfate solution, the organig phase was separated, dried and evaporated. The residue was purified by chromatography on silica gel to give 155 g of the desired product.
Reaction SMILES: N1C=CC=C([C:7]([C:9]2[C:10]([C:15](OC)=O)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])C=1.O.[NH2:20][NH2:21]>C(O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=1[C:15]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:7](=[O:8])[NH:21][N:20]=1
Reactant: COC(=O)c1ncccc1C(=O)c1cccnc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccccn2)c2ncccc12
Temperature: 75 °C
Yield: 135.4 %

Procedure:
A mixture of methyl 3-picolinoylpicolinate 7, (240 mg, 0.99 mmol), hydrazine hydrate (63 μL, 1.3 mmol) and 12 mL of absolute ethanol was heated to 75° C. in a sealed tube for 1 h. After cooling, the solid was collected by vacuum filtration and dried under air suction. The mother liquor was concentrated to dryness under reduced pressure and purified by normal phase flash chromatography eluting with 0-10% methanol in dichloromethane over approximately 20 minutes. Like fractions were combined and concentrated under reduced pressure and combined with the solid collected by filtration to give 8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one 9 (150 mg, 0.67 mmol). 1H NMR (400 MHz, Methanol-d4) δ 9.07 (dd, J=4.5, 1.6 Hz, 1H), 8.98 (dd, J=8.4, 1.6 Hz, 1H), 8.72 (ddd, J=4.9, 1.7, 1.0 Hz, 1H), 8.00 (ddd, J=7.9, 7.3, 1.7 Hz, 1H), 7.99-7.92 (m, 1H), 7.97-7.84 (m, 1H), 7.53 (ddd, J=7.3, 4.9, 1.5 Hz, 1H). LCMS: (M+H)+, 225.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([NH:18]C(OC(C)(C)C)=O)([CH3:17])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([NH2:18])([CH3:17])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1(N)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Yield: 84.6 %

Procedure:
To 74 g (149 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-carbo-t-butoxyamino-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 2) was added 74 g of trifluoroacetic acid and 74 g of chloroform. The mixture was refluxed for 40 minutes while gas was evolved and then an additional 20 minutes. The mixture was then concentrated in vacuo and then partitioned between ethyl ether and dilute aqueous sodium hydroxide. The organic layer was washed with brine, dried over magnesium sulfate, concentrated in vacuo, and the resulting solid was triturated with hexanes and filtered yielding 50 g (85%) of a white solid, mp 165°-167° C.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:43])=[O:3])=[C:10]([CH2:36][CH:37]4[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]4)[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(CC2CCCCC2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid ethyl ester (0.54 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (0.4 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH 1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.03-8.05 (m, 2H), 7.67 (d, 2H, J=8.8 Hz) 7.62 (d, 2H, 6.8 Hz), 7.47-7.43 (m, 2H), 7.35-7.39 (m, 1H, J=8.8 Hz), 6.67 (d, 1H, J=29 Hz), 6.62 (dd, 1H, J=8.8 Hz, J=2.9 Hz), 4.18 (t, 2H, J=6.4 Hz), 3.00 (t, 2H, J=6.4 Hz), 2.40 (s, 3H), 1.62-1.66 (m, 5H), 1.53 (s, 6H), 1.25 (s, 2H), 1.13-1.18 (m, 4H), 0.85-0.97 (m, 2H), MS (ES) m/e 554.2 (M+1).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[F:22][C:23]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][C:24]=1[C:25]#[N:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:29]=[CH:30][C:23]=2[F:22])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCCc1ccc(F)c(C#N)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCc1ccc(F)c(-c2nc(-c3ccccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (1.27 g), 2-fluoro-5-undecylbenzonitrile (1.09 g), anhydrous aluminum chloride (0.55 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.85 g of desired compound (melting point: 35.0°-37.0° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)=[O:8].[NH:19]1[CH2:23][CH2:22][C@H:21]2[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][C@@H:20]12>>[F:17][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C:6]2[CH:18]=[C:2]([N:19]3[C@H:20]4[C@H:21]([CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]4)[CH2:22][CH2:23]3)[CH:3]=[N:4][CH:5]=2)=[O:8])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCN[C@@H]2C1
Reactant: O=C(Nc1cc(F)cc(F)c1)c1cncc(Br)c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCN(c3cncc(C(=O)Nc4cc(F)cc(F)c4)c3)[C@@H]2C1

Procedure:
The product from Example 53A and (3aS,6aS)-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (prepared as described in WO2001081347) were processed as described in Example 53B to provide the title compound. MS (APCI) m/z=445 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][NH:29][C:30]([CH2:32][N:33]([S:41]([CH3:44])(=[O:43])=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)=[O:31]>>[CH3:28][NH:29][C:30]([CH2:32][N:33]([C:34]1[CH:35]=[CH:36][C:37]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:38][CH:39]=1)[S:41]([CH3:44])(=[O:43])=[O:42])=[O:31]
Reactant: CNC(=O)CN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CNC(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-methylaminocarbonylmethyl-N-methylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C27H26N4O6S
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:38][C:39]([Cl:43])=[C:40]([NH2:42])[CH:41]=1)(=[O:36])=[O:35])([CH3:32])[CH3:31]>>[Cl:43][C:39]1[S:38][C:37]([S:34](=[O:36])(=[O:35])[NH:33][C:30]([CH3:31])([CH3:32])[CH2:29][OH:28])=[CH:41][C:40]=1[NH:42][C:25]([C:24]1[CH:23]=[N:22][N:15]2[C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[CH:3]=3)=[N:13][C:14]=12)=[O:26]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([CH2:48][O:49][CH2:50][C@H:51]2[CH2:55][O:54]C(C)(C)[O:52]2)[CH2:9]1)=O)(C)(C)C.C(=O)([O-])O.[Na+].[OH-].[Na+]>CO.Cl.ClCCl>[CH3:47][O:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH2:39][O:38][CH2:37][CH2:36][CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:11]2[C@@H:12]([O:14][CH2:15][C:16]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:13][NH:8][CH2:9][C@H:10]2[CH2:48][O:49][CH2:50][C@H:51]([OH:52])[CH2:55][OH:54])=[CH:29][CH:30]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](COC[C@H]3COC(C)(C)O3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](COC[C@H](O)CO)CNC[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1
Temperature: 0 °C

Procedure:
A solution of 4.7 g (6 mmol) of (3S,4R,5R)-3-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester in 50 ml of methanol and 44.4 ml of 2.7M hydrogenchloride in methanol was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was cooled to 0° C. and 20.1 g (239 mmol) of solid sodium hydrogencarbonate were added. Stirring was continued as long as carbondioxide was formed and the reaction mixture had reached room temperature. Then the mixture was adjusted to pH 8-9 by addition of 2 N sodium hydroxide solution and diluted with 250 ml of dichloromethane. The aqueous phase was separated and the organic phase dried over sodium sulfate and finally evaporated under reduced pressure. The residue which was thereby obtained was chromatographed on silica gel with a 90:10:0.1 mixture of dichloromethane, methanol and ammonium hydroxide as the eluent. There where thus obtained 2.7 g of (R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol in the form of an amorphous solid MS: 646 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:6]=1)[C:2]#[CH:3].[N:27]([CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[N+:28]=[N-:29].C1CCN2C(=NCCC2)CC1>CO.[Cu]I>[N:32]1([CH2:31][CH2:30][N:27]2[CH:3]=[C:2]([CH2:1][NH:4][C:5]3[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:17][CH:16]=4)[CH:6]=3)[N:29]=[N:28]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C#CCNc1cc(Nc2ccc(C3CCOCC3)cc2)ncc1C(N)=O
Reactant: [N-]=[N+]=NCCN1CCCCC1
Agent: [Cu]I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC(=O)c1cnc(Nc2ccc(C3CCOCC3)cc2)cc1NCc1cn(CCN2CCCCC2)nn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Compound 4-(prop-2-ynylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide (Example 184) (20 mg, 0.057 mmol) was dissolved in 6 mL MeOH. To it were added 1-(2-azidoethyl)piperidine (18 mg, 0.11 mmol), DBU (26 μL, 0.17 mmol) and finally powder CuI (13 mg, 0.068 mmol). The mixture was stirred at RT for 5 h, filtered and subjected to reverse phase prep HPLC to isolate the title compound. MS found for C27H36N8O2 as (M+H)+ 505.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.14 (1H, s), 8.12 (1H, s), 7.39 (2H, dt, J=8.4; 2.0 Hz), 7.24 (2H, dt, J=8.4; 2.0 Hz), 6.20 (1H, s), 4.60 (2H, s), 4.05 (2H, m), 3.73 (2H, m), 3.59 (4H, m), 3.04 (2H, m), 2.87 (1H, m), 1.95 (2H, m), 1.86-1.75 (8H, m) ppm.
Reaction SMILES: [Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCCCC.[Cl:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31].[F-:35].[K+]>ClC1C=CC=CC=1Cl>[Cl:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1[F:35].[Cl:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: [F-]
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Temperature: 180 °C
Yield: 77 %

Procedure:
70 g of octadecyltrimethylammonium chloride are dissolved at 70° C. in 2020 g (10.5 mol) of 3,4-dichloronitrobenzene and 100 g of o-dichlorobenzene. After addition of 580 g (10 mol) of potassium fluoride, the resulting suspension is heated for 11 hours at 180° C. with stirring and under nitrogen. During this time, some of the o-dichlorobenzene is continuously distilled off. The reaction suspension is then quickly filtered off using suction, the filter cake is washed with o-dichlorobenzene and the combined filtrates are fractionated in vacuo. In this manner 1349 g (77% of theory) of 3-chloro-4-fluoronitrobenzene and 246 g of unreacted 3,4-dichloronitrobenzene are obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:28]=[CH:27][C:9]([CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:17]([C:21](Cl)=[O:22])=[N:16][CH:15]=[C:14]([O:24][CH3:25])[C:13]=3[C:12]2=[O:26])=[CH:8][CH:7]=1>O.CC(C)=O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:17]([C:21]([N:1]=[N+:2]=[N-:3])=[O:22])=[N:16][CH:15]=[C:14]([O:24][CH3:25])[C:13]=3[C:12]2=[O:26])=[CH:27][CH:28]=1
Reactant: COc1cnc(C(=O)Cl)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cnc(C(=O)N=[N+]=[N-])c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 0.33 h

Procedure:
To a solution of sodium azide (0.24 g, 3.69 mmol) in water (2.5 mL) was added 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonyl chloride (1.17 g, 3.36 mmol) in acetone (15 mL). After 20 minutes, the product mixture was concentrated under vacuum to provide 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonyl azide. The crude azide (1.19 g, 3.35 mmol) in DMF (20 mL) was heated to 110° C. After 20 minutes, the product mixture was cooled for 10 minutes, then 1N NaOH (3.3 mL) was added. After 20 minutes, the mixture was concentrated under vacuum, re-dissolved in toluene and CHCl3 and evaporated. The residue was partitioned between CHCl3 and saturated sodium bicarbonate. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([C:22]2([O:28][CH3:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:21]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:17][NH2:18])[CH:11]=[CH:10]2.[CH3:30][C:31]([CH3:33])=O>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([C:22]2([O:28][CH3:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:21]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]1[C:31]([CH3:33])([CH3:30])[NH:18][N:17]=[C:12]1[CH:11]=[CH:10]2
Reactant: CC(C)=O
Reactant: COC1(c2cc(F)cc(OCc3ccc4nc(NN)ccc4c3)c2)CCOCC1
Solvent: CCO
Product: COC1(c2cc(F)cc(OCc3ccc4c(c3)C=CC3=NNC(C)(C)N34)c2)CCOCC1
Temperature: 75 °C

Procedure:
{6-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-quinolin-2-yl}-hydrazine (36 mg, 0.09 mmol) was suspended in EtOH (2 mL). Acetone (0.01 mL, 0.18 mmol) was added, and the reaction was heated at 75° C. overnight. The mixture was concentrated and purified by silica gel chromatography to give the desired product, 6a.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11](=[O:20])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.C[Si]([I:32])(C)C.II>C(Cl)Cl>[I:32][CH:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[NH:12][C:11]1=[O:20]
Reactant: C[Si](C)(C)I
Reactant: COc1ccc(C2CC(=O)Nc3ccccc3C2)cc1
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2Cc3ccccc3NC(=O)C2I)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (-20° C.) solution of 500mg (1.87mmole) of 2,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1H-1-benzazepin-2-one in 10 mL of methylene chloride was added triethylamine (1.04g, 9.35 mmol, 5eq.) followed by trimethylsilyl iodide (749mg, 3.74mmol, 2eq.). After 15 minutes, 950 mg (3,74 mmol, 2eq) of iodine was added and the brown mixture was stirred at 0° C. for one hour. The reaction mixture was diluted with methylene chloride, washed with aqueous sodium bisulfite solution, water and brine and then dried (MgSO4). Filtration followed by evaporation of the solvent under vacuum gave the product as a mixture of cis and trans isomers (675 mg,92%). FAB-MS: calculated for C17H16NO2I 393; found 393 (100%), 394 (20%).
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:3]1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][N:4]1[CH2:3][CH:2]([OH:1])[C:6]2([CH2:7][CH2:8]2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCN1CC(O)C2(CC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propanol (1.14 g, 6.67 mmol) and Et3N (1.35 g, 13.34 mmol) in CH2Cl2 (20 mL) was added methanesulfonyl chloride (1.15 g, 10 mmol) dropwise at 0° C. The reaction was then stirred at 0° C. for 3 hrs. The reaction mixture was washed with cold water (10 mL) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound as orange oil. The crude product was used for the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl.CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
4-iodophenylacetic acid (5.2 g, 0.02 mol) and DMAP (0.25 g, 0.002 mol) was dissolved in dichloromethane (40 mL) and methanol (3.2 mL), and the solution was cooled to 0° C. Then a solution of DCC (4.32 g, 0.021 mol) in dichloromethane was added dropwise over a period of 15 minutes. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 16 hours, then filtered. The filtrate was diluted with dichloromethane (40 mL) and washed with 5% citric acid (4×25 mL), water (2×50 mL), dried (Na2SO4), filtered, and concentrated. The residual liquid was purified by silica gel flash column chromatography eluting with 20% EtOAc in hexane to give methyl 4-iodophenylacetate (4.5 g, 82%) as a colorless liquid: 1H-NMR (CDCl3) δ: 7.64 (d, 2H, J=8.4 Hz), 7.01 (2H, J=8.4 Hz), 3.69 (s, 3H), 3.57 (s, 2H); FAB-MS m/z=283 (M+Li). HRMS calcd. for C9H10IO2 (M+H), 276.9725, found 276.9726.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:11][C:12]([F:16])([F:15])[CH2:13]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:13][C:12]([F:16])([F:15])[F:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Yield: 838.3 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (3.1 g, 2 mmol), 1,1,1-trifluoro-2-iodo-ethane (2.4 mL, 24 mmol), K2CO3 (5.5 g, 40 mmol) and KI (0.1 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 180° C. for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give title compound as a yellow solid (Yield: 4 g).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[NH2:31])=[CH:26][C:25]=1[N+:33]([O-:35])=[O:34])([CH3:23])([CH3:22])[CH3:21].O>O1CCCC1.CCCCCC>[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=1[N+:33]([O-:35])=[O:34])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(C(N)=O)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)c1ccc(C#N)cc1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
3.3 ml of pyridine and then 4.3 ml of trifluoroacetic anhydride were added to a solution of 2.25 g (10.1 mmol) of 2-t-butyl-5-carbamoyl-1-nitrobenzene [prepared as described in Preparation 38(i)] in 20 ml of tetrahydrofuran, and the resulting mixture was stirred for 20 minutes. The reaction mixture was then mixed with water, and the aqueous mixture was extracted with a mixture of ethyl acetate and hexane. The extract was washed with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 50 g of silica gel to give 1.99 g (yield 96%) of the title compound as crystals, melting at 70.5°-71.5° C. (from hexane).