Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].[I-].[Na+]>CC(=O)CC>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:10]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(CN(c2ccc([N+](=O)[O-])cc2)n2cnnc2)cc1
Yield: 45.6 %

Procedure:
To a suspension of 0.37 g of 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole obtained in Referential Example 3 in 20 ml of 2-butanone were successively added 0.83 g of potassium carbonate anhydride, 1.30 g of p-nitrobenzyl bromide and a catalytic amount of sodium iodide, at room temperature, and the reaction mixture was then heated under reflux for about 2 hours. After cooled, the solvent was removed by distillation under reduced pressure, and a proper amount of water was added to the residue, which was then extracted several times each with ethyl acetate. The ethyl acetate layer separated was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue formed was purified by silica gel column chromatography to give crude crystals from the chloroform/methanol (100/1) eluate. The crude crystals thus obtained were recrystallized from ethanol to give 0.28 g of 4-[N-(4-nitrobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][N:25]=1.C1N2CCN(CC2)C1>C(#N)C>[N:27]1[CH:28]=[CH:29][C:24]([NH:23][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:22])([F:21])[F:1])[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[N:25][CH:26]=1
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Reactant: Nc1ccncn1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=C(N1CCC(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CC1)C(F)(F)F
Temperature: 40 °C
Yield: 36.6 %

Procedure:
Prepared using general procedure 15, method B. Prepared using a mixture of 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chloride (2.0 g, 5.6 mmol), 4-aminopyrimidine (535 mg, 5.6 mmol), DABCO (3.1 g, 28.0 mmol) and acetonitrile (10 mL). The reaction mixture was heated at 40° C. for 6 h. Purification via silica gel chromatography using 5% MeOH in CH2Cl2 gave N-(pyrimidin-4-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide (850 mg, 36%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=415.3; tR=2.57 min.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]=[C:7]2[CH2:15][C:14]34O[CH:13]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:8]2=O)=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][NH2:30])[CH2:22][CH2:21]1.C(O)(=O)C.Cl>CCO.CC#N>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[N:29]([CH2:28][CH2:27][CH2:26][N:23]3[CH2:22][CH2:21][O:20][CH2:25][CH2:24]3)[N:30]=[C:8]3[C:9]4[C:14]([CH2:15][C:7]=23)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccc(Cl)cc2)CC23OC2C=CC=C13
Reactant: NNCCCN1CCOCC1
Agent: Cl
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCO
Product: Clc1ccc(-c2c3c(nn2CCCN2CCOCC2)-c2ccccc2C3)cc1
Yield: 134.7 %

Procedure:
Interaction of 16.1 g (0.059 mole) of 2-(p-chlorobenzylidene)-1-indanone oxide and 10.0 g (0.063 mole) of 3-morpholinopropylhydrazine in 285 ml of EtOH in the presence of 9.6 ml of glacial acetic acid as described in Example 1 yields 20.2 g of crude base as a yellow-orange viscous syrup. The latter is dissolved in 150 ml of warm MeCN, cooled, and treated with 9.3 ml of 5.5 N alcoholic HCl. After filtering a small amount of solid which has separated, the solution is diluted to 550 ml with ether. On rubbing, the crystalline HCl salt rapidly separates. After cooling overnight, the pale yellow solid weighs 20.1 g (78%); m.p. 174°-177° (s. 80°). Crystallization from 60 ml of MeCN gives 17.1 g of cream-colored material; m.p. 181°-183° (s. 140°). Following recrystallization from 60 ml of MeCN, the nearly colorless product weighs 13.7 g (53%); m.p. 181°-183°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH2:27]([O:29][C:30](=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:9]1[N:13]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[C:12]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=2[N:10]=1)[CH3:28]
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: CCOC(=O)CCCCCBr
Product: CCOC(=O)CCCCCOc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and (6-bromo-hexanoic acid ethyl ester CAS Reg. No. 25542-62-5). Brown sticky solid (70%). MS (Turbo Spray): m/z=519.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20])[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:28])[C@@H:19]([NH:20][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:16]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 2.00 g, 10.2 mmol) in DMF (50 mL) was added L-phenylalanine ethyl ester hydrochloride (2.45 g, 10.7 mmol), HOBt (1.37 g, 10.2 mmol) and DIPEA (5.3 mL, 30.5 mmol). After 5 min, EDCI (2.54 g, 13.2 mmol) was added and the reaction mixture stirred at rt for 16 h. The solvent was removed in vacuo and the solid dissolved in ethyl acetate (150 mL) and washed with water (200 mL). The organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol/dichloromethane (3:97) to give the title compound as a pale yellow solid. δH (CD3OD): 1.21 (3H, t), 3.13 (1H, dd), 3.28 (1H, dd), 4.17 (2H, q), 4.86 (1H, m), 7.09 (1H, s), 7.16-7.26 (5H, m), 7.65 (1H, s), 8.55 (1H, s); m/z (ES+)=372 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:15]=3[CH:16]=2)[NH:11][C:10](=[O:21])[C:9]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[C:27](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>O>[CH3:27][N:11]1[C:12]2[C:17](=[CH:16][C:15]3[CH2:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[C:9]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:21]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2[nH]c1=O)CCC3
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2n(C)c1=O)CCC3
Temperature: 25 °C
Reaction time: 10 h
Yield: 94.5 %

Procedure:
To a mixture of ethyl 4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (3.0 g), potassium carbonate (1.43 g) and DMF (30 ml) was added methyl iodide (0.65 ml) dropwise. The mixture was stirred at room temperature for 10 hours, after which water was added to the reaction mixture to give crystals of ethyl 1-methyl-4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (2.95 g, 94.6%). Recrystallization from ethyl ether-isopropyl ether gave colorless needles, m.p. 134°-135° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[N:36]=[CH:37][C:30]=12)[C:24]([O:26]C)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1C=CC=CC=1)[C:2]1C=CC=CC=1.[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([NH2:52])=[N:50][CH:51]=1>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[C:30]2[CH:37]=[N:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[C:31]=2[N:32]=[CH:33][N:34]=1)[C:24]([NH:52][C:49]1[CH:48]=[CH:47][C:46]([Cl:45])=[CH:51][N:50]=1)=[O:26])([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:8])[CH3:2]
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1ccccc1Cl
Product: CC(C)(C)[Si](C)(C)OCCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccc(Cl)cn1

Procedure:
Prepared from (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AG2) (950 mg, 1.51 mmol) according to the method for Intermediate AE3 using 5-chloropyridin-2-amine. 1H NMR (400 MHz, DMSO) δ 0.88 (9H, s), 3.71-3.84 (4H, m), 4.02-4.07 (1H, m), 4.13-4.18 (1H, m), 5.97-5.99 (1H, m), 7.34-7.43 (6H, m), 7.56-7.67 (7H, m), 7.74-7.77 (1H, m), 7.86-7.89 (1H, m), 8.00-8.03 (1H, m), 8.40-8.41 (1H, m), 8.52 (1H, s), 8.57 (1H, s), 11.25 (1H, s); m/z (ESI+) (M+H)+=727; HPLC tR=3.49 min.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:13])(=O)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:8][CH:7]([Cl:13])[O:6][C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCOC1=O
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N1CC(Cl)OC1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5.00 g of 3-acetyloxazolidin-2-one were initially charged in 25 ml of carbon tetrachloride and heated to 70° C. under an argon atmosphere. Then, alternately, a solution of 3.46 ml of sulfuryl chloride in 5 ml of carbon tetrachloride and 0.10 g of 2,2′-azobis(2-methylpropionitrile) were added, and then the mixture was stirred at the same temperature for 2 hours. After cooling to room temperature, the clear solution was decanted off from the solid residues, and the solvent was removed under reduced pressure. This gave the product (6.80 g) with a molecular weight of 163.6 g/mol (C5H6ClNO3).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[Cl-].[C@@H:32]12[NH:47][C@@H:36]([CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]1)[CH2:35][O:34][CH2:33]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:47]5[C@H:32]6[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:37][C@@H:36]5[CH2:35][O:34][CH2:33]6)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2COC[C@@H](C1)N2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Agent: [Cl-]
Agent: [Li+]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4[C@@H]5COC[C@H]4CN(C(=O)OC(C)(C)C)C5)cn3)nc2n1C1CCCC1
Yield: 85 %

Procedure:
Following general amide formation method 2, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid with 5 equiv LiCl and (1R,5S)-tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate were combined and gave (1R,5S)-tert-butyl 9-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (115 mg) in 85% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.78 (s, 1H), 8.60 (d, J=9.09 Hz, 1H), 8.44 (d, J=2.02 Hz, 2H), 7.85 (dd, J1=8.59 Hz, J2=2.02 Hz, 1H), 6.49 (s, 1H), 4.82 (m, 1H), 4.59-3.75 (m, 6H), 3.17 (s, 4H), 3.02 (s, 2H), 2.95 (s, 2H), 2.81 (m, 4H), 2.57 (m, 1H), 2.09 (m, 4H), 1.75 (m, 1H), 1.49 (m, 9H) LCMS m/z 604.9 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1.[CH2:14]([NH2:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[I-].[K+]>C(O)C>[CH3:13][S:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:22][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7][CH:8]=1
Reactant: CCCCCCCCN
Reactant: CSc1ccc(OCCCCl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCNCCCOc1ccc(SC)cc1
Yield: 22 %

Procedure:
A solution of 1-chloro-3-[4-(methylthio)phenoxy]propane (5.0 g., 0.023 mole) in 30 ml. of ethanol is treated with n-octylamine (2.84 g., 0.022 mole) and 30 mg. of potassium iodide. After refluxing for a period of 18 hrs., the reaction mixture is concentrated to dryness under reduced pressure, treated with 3N potassium hydroxide solution and ether, and the layers separated. The ether layer is washed with water, concentrated under reduced pressure, and heated on a steam bath at 0.1 mm Hg pressure to remove residual n-octylamine. The residue of N-[3-[4-(methylthio)phenoxy]propyl]octylamine base thus obtained is dissolved in ethanol, treated with excess 6N hydrochloric acid and activated charcoal, filtered and concentrated to dryness under reduced pressure. Crystallization of the residue from isopropyl alcohol-ether affords 1.7 g. (22% yield) of analytically pure N-[3-[4-(methylthio)phenoxy]propyl]octylamine hydrochloride, m.p. 214.5°-215.5° C. (corr.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].[Cl:20][C:21]([Cl:25])=[CH:22][CH2:23]Cl>CN(C)C=O>[Cl:20][C:21]([Cl:25])=[CH:22][CH2:23][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Reactant: ClCC=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CC=C(Cl)Cl)Cc1ccc(OC(F)(F)F)cc1
Yield: 28 %

Procedure:
Using 0.20 g of (4-(trifluoromethoxy)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 50 mg of sodium hydride (60% in oil), and 0.17 ml of 1,1,3-trichloropropene, and according to the process described in the Production Example 1, there was obtained 80 mg of 2-(3,3-dichloro-2-propenyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (28)).
Reaction SMILES: [O:1]=[C:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][O:10][C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(O)C.C(OCC)(=O)C.[C].[Pd]>[O:1]=[C:2]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][O:10][C:11]2[N:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccc(OCC(=O)c3ccccc3)cc2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1ccc(OCc2ccc(OCC(=O)c3ccccc3)cc2)nc1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A solution of ethyl (2E)-3-(6-{[4-(2-oxo-2-phenylethoxy)benzyl]oxy}pyridin-3-yl)prop-2-enoate (0.13 g, 0.31 mmol) in ethyl acetate ethanol mixture was degassed well and added palladium carbon (10 mg), and stirred under hydrogen bladder for 3 hrs. Reaction mass was filtered through celite pad and concentrated to a colourless oil (0.12 g, Yield: 95%); MS (ESI, 120 eV): m/z=420 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([CH2:29][NH:30][CH3:31])[C:26]([O:32]COCC[Si](C)(C)C)=[C:25]([O:41][CH3:42])[CH:24]=2)[N:20]=[N:19][C:18]=1[O:43]C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:32][C:26]1[C:27]([CH2:29][NH:30][CH3:31])=[CH:28][C:23]([C:21]2[CH:22]=[C:17]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:18](=[O:43])[NH:19][N:20]=2)=[CH:24][C:25]=1[O:41][CH3:42]
Reactant: CNCc1cc(-c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(OC)nn2)cc(OC)c1OCOCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cc(OC)c1O
Temperature: 85 °C

Procedure:
118 mg of 2-{3-Methoxy-6-[3-methoxy-5-methylaminomethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-pyridazin-4-yl}-indole-1-carboxylic acid tert-butyl ester is dissolved in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid and the solution is stirred for 4 h at RT. The solvents are removed under reduced pressure. The residue is dissolved in 26 ml of acetonitrile and 117 mg of potassium iodide and 76 mg of chlorotrimethylsilane are added. The reaction is heated to 85° C. for 3 h. The reaction is quenched by the addition of a drop of water, the solvent is removed under reduced pressure and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 13 mg. LC-MS (ES+) 377 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:21]2[CH:37]=[CH:36][C:24]([O:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:23][CH:22]=2)[C:17](NO)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)[C:40](O)=[O:41]>ClCCl>[NH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C@@H:16]([NH:15][S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[C:17]([O:41][CH3:40])=[O:18])=[CH:37][CH:36]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)NO)c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCN)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.300 g (0.564 mmol) of methyl (2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-butynyloxy)phenyl]sulfonyl}-amino)ethanoate (from Example 199) in 1.5 mL of dichloromethane was added 1.5 mL of trifluoroacetic acid and the resulting mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The residue was diluted with ethyl acetate and the organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to provide 0.244 g of methyl(2R)-[4-(2-aminoethoxy)phenyl]({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate pure enough for use in the next step. Electrospray Mass Spec 433.3 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[Cl:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([C:2]2[C:3]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:4][C:5]([C:18]([F:19])([F:20])[F:21])=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(-c2ccc(Cl)c(Cl)c2)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(pyridin-2-ylmethoxy)-2-trifluoromethyl-nicotinamide and 3,4-dichlorophenylboronic acid as starting materials, MS (ISP) 540.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([F:26])[CH:3]=1.[OH-].[Na+].[NH2:29]O.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([F:26])[CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
Trans-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (500 mg, 1.30 mmol) (from example 45, step 1) was dissolved in MeOH (6 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.381 mL, 1.30 mmol) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.079 mL, 1.30 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (6.67 mL, 40.05 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.45 g, 98%) as a slightly yellow dry film. MS m/z 355 (M+H)+
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([C:16](O)=[O:17])[C:7]=1[O:19][CH3:20].[NH4+:21].[OH-]>C1(C)C=CC=CC=1.CN(C=O)C>[I:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([C:16]([NH2:21])=[O:17])[C:7]=1[O:19][CH3:20]
Reactant: [NH4+]
Reactant: COc1c(C(=O)O)cc2c(c1I)CCCC2
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1c(C(N)=O)cc2c(c1I)CCCC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (1.59 mL, 21.80 mmol) was added dropwise over 5 min to a stirred suspension of 4-iodo-3-methoxy-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid (2.9 g, 8.73 mmol) in toluene (10 mL) and DMF (0.25 mL) at room temperature. After heating at reflux for 3.5 h, the reaction was cooled to 0° C. and added to cooled (0° C.) 28% NH4OH (25 mL). The mixture was stirred at 0° C. for 10 min and at room temperature overnight. The mixture was filtered and the collected solid was thoroughly washed with H2O. The light brown solid (2.07 g, 72%) was dried under high vacuum at 50° C. 1H NMR (CDCl3) δ 7.79 (s, 1H), 7.61 (s, 1H), 5.90 (s, 1H), 3.84 (s, 3H), 2.76 (m, 4H), 1.79 (m, 4H). MS m/z 332 (M+H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[C:28](=[O:29])[C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[C:25](=[O:34])[C:24]=1[CH3:35])(=[O:11])[CH3:10]>CCOCC.O>[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[C:28]([OH:29])=[C:27]([O:30][CH3:31])[C:26]([O:32][CH3:33])=[C:25]([OH:34])[C:24]=1[CH3:35])(=[O:11])[CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCOC(C)=O)=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1c(O)c(C)c(CCCCCCCCCCOC(C)=O)c(O)c1OC

Procedure:
2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-1,4-benzoquinone (3.38 g) was dissolved in dichloromethane (50 ml). Pyridine (1 ml) was added, and acetyl chloride (0.8 ml) was added with stirring under ice-cooling. After stirring for 1 hour at the same temperature, the mixture was washed with 0.1N hydrochloric acid (50 ml) followed by water (50 ml). The dichloromethane layer was concentrated under reduced pressure to obtain 6-(10-acetoxydecyl)-2,3-dimethoxy-5-methyl-l,4-benzoquinone as a red oil. This oil was dissolved in ether (50 ml), and a solution of sodium hydrosulfite (4 g) in water (50 ml) was added. Stirring was continued at room temperature until the red color of the ether layer disappeared. The ether layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired compound (3.8 g) as a pale yellow oil.