Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:34]=[C:33]([CH2:32][CH2:31][OH:35])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CCO)cc3cc(CC4CCOCC4)cc(c1=O)c32
Yield: 71 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxamide (0.16 g), PdCl2(PPh3)2, CuI (0.018 g) and 3-butyn-1-ol (0.03 mL) in 15 mL Et2NH is stirred at room temperature for 7 days. The solid in the reaction is filtered and rinsed with EtOAc. The filtrate is partitioned between EtOAc and H2O. The aqueous layer is extracted with EtOAc (3×). The organic layers and the solid previously filtered are combined, concentrated, adsorbed onto silica and chromatographed (gradient from CH2Cl2 to 4% MeOH in CH2Cl2). Product-containing fractions are combined and condensed to afford 101.6 mg (71%) of N-(4-chlorobenzyl)-2-(2-hydroxyethyl)-6-oxo-8-(tetrahydro-2H-pyran-4-ylmethyl)-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a tan solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NCC(c1ccc(F)cc1)c1ccc(F)cc1
Product: Fc1ccc(C(CNc2nc3ccccc3[nH]2)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2,2-bis(4-fluorophenyl)ethylamine (prepared by Procedure B from 2,2-bis(4-fluoro-phenyl)acetaldehyde) by Procedure A (20 min at 170° C.). The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 155-157° C.). MS(ES+) m/z 350 ([M+1]+, 100) 1NMR (DMSO-d6) δ 3.90 (m, 2H), 4.46 (t, 1H), 6.50 (m, 1H), 6.80-6.90 (m, 2H), 7.07-7.18 (m, 6H), 7.35-7.42 (m, 4H), 10.5 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5](OC)([O:8][CH3:9])[O:6][CH3:7].C[O-].[Na+]>>[CH3:7][O:6][Si:5]1([O:8][CH3:9])[CH2:4][CH2:3][CH2:2][NH:1]1
Reactant: CO[Si](CCCN)(OC)OC
Agent: C[O-]
Agent: [Na+]
Product: CO[Si]1(OC)CCCN1
Temperature: 130 °C

Procedure:
The procedure of Example 1 was repeated, except that 3-aminopropyltrimethoxysilane (113.5 grams; 0.63 moles) was used. Sodium methoxide (2.3 grams, 2 wt.%) was added. The reaction mixture was stirred and heated to 90° C. to 98° C. for 6 hours at 4-8 mm Hg, while slowly removing distillate. However gas chromatographic analysis indicated 1,1-dimethoxysila-2-azacyclopentane was not formed. The distillate consisted of >99% 3-aminopropyltrimethoxysilane. The reaction mixture was further heated to 130° C. (>10 mm Hg) but distillate analysis again indicated no five-membered ring cyclosilazane product was formed.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH:21]1([CH2:26][CH2:27]Br)[CH2:25][CH2:24][CH:23]=[CH:22]1>>[CH:21]1([CH2:26][CH2:27][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:25][CH2:24][CH:23]=[CH:22]1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCCC1C=CCC1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2CCC2C=CCC2)c1
Yield: 35.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-(cyclopent-2-en-1-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound (132 mg).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:26])=[CH:22][C:23]=4[F:25])[N:18]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN.Cl>ClCCl.CO.ClCCl.O1CCOCC1.C(OCC)(=O)C.O>[ClH:26].[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:26])=[CH:22][C:23]=4[F:25])[N:18]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN(C)C)c4cc(Cl)cc(F)c34)nc12
Agent: Cl
Solvent: NCCN
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCN(C)C)c4cc(Cl)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.9 %

Procedure:
2-[6-Chloro-1-(2-dimethylamino-ethyl)-4-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (35 mg, 0.06 mmol) was dissolved in dichloromethane (1.6 ml) and cooled in ice bath. Trifluoroacetic acid (0.8 ml) was slowly added and the reaction was stirred at room temperature for 2 h. The reaction was evaporated and the residue was dissolved in dichloromethane (1 ml). Ethylenediamine (0.25 ml, 3.7 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (methanol/dichloromethane). The product thus isolated was dissolved in methanol/dichloromethane and treated with 4 eq of 4 M HCl in 1,4-dioxane. Evaporation of the solvent provided a solid which was dried under high vacuum to afford 18 mg (62%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-4-fluoro-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide hydrochloride. MS: (M+H)+=444; mp=281-283° C. 1H NMR (300 MHz, DMSO-d6) δ: 10.17-10.33 (m, 1H), 9.08 (s, 1H), 8.44 (d, J=3.0 Hz, 1H), 8.26 (d, J=7.9 Hz, 1H), 8.03-8.08 (m, 1H), 7.34 (d, J=10.6 Hz, 1H), 4.94-5.05 (m, 2H), 4.14-4.30 (m, 1H), 3.66-3.77 (m, 2H), 2.89 (d, J=4.5 Hz, 6H), 1.24 (d, J=6.8 Hz, 6H).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].[CH:24]1([C:27]2[C:28]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=2)[CH2:26][CH2:25]1>>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:21])=[O:22])[CH:13]=[CH:12][C:8]=1[C:9]([N:40]1[CH2:41][CH2:42][N:37]([C:28]2[C:27]([CH:24]3[CH2:25][CH2:26]3)=[CH:32][C:31]([C:33]([F:36])([F:34])[F:35])=[CH:30][N:29]=2)[CH2:38][CH2:39]1)=[O:10]
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 47.2 %

Procedure:
Using 2,4-bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 34 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (150 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 87, the title compound (160 mg) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:25][NH2:26]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:26][CH3:25])[S:8]1(=[O:24])=[O:23]
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccccc1F
Reactant: CN
Product: CNCCOCCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Yield: 95 %

Procedure:
In an analogous manner as described in general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.07 g, 0.16 mmol) was treated with methylamine (10 mL) to provide 0.05 g (95%) of 2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N-methylethanamine. MS (ES) m/z 366.0; HRMS: calculated for C17H20FN3O3S+H+, 366.12822; found (ESI, [M+H]+), 366.1285; HPLC purity 100.0% at 210-370 nm, 8.4 minutes; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40]([O-:42])=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34].[BrH:45]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12][CH:10]1[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([O-:42])=[O:41])=[CH:43][CH:44]=1)([O-:35])=[O:34].[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12][C@H:10]1[Br:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Agent: C[C@@H]1OC(O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=C([O-])c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: C[C@@H]1O[C@@H](Br)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
Similarly, treatment of the β-isomer of the fucopyranosyl-p-nitrobenzoate (compound 8) (583 mg, 1 mmol) with a saturated solution of HBr in CH2Cl2 (5 mL) for 30 min at 5° C. furnished the α-fucopyranosyl bromide (550 mg). The NMR spectrum of this product was identical with that of α-bromide obtained earlier from the α-fucopyranosyl p-nitrobenzoate. However, due to the instability of the bromide, it was used as such immediately for the next step. 1H-NMR (CDCl3): 1.17 (d, 3H, J=6.45 Hz, CH3), 3.6-4.2 (m, OCH), 4.8-5.02 (m, OCH2), 6.53 (d, 1H, OCHBr), 7.2-7.5 (15H, Ar—H); 13C-NMR (CDCl3): 16.61 (CH3), 72.36 (OCH), 73.23 (OCH2), 74.00 (OCH2), 75.59 (OCH2), 76.57 (OCH), 74.49 (OCH), 80.02 (OCH), 95.26 (OCHBr), 127.97, 128.09, 128.23, 128.32, 128.43, 128.75, 128.86 (aromatic carbons).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([O:37][CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([O:37][CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:24])=[O:25])[CH:21]=2)[CH:5]=[CH:4][N:3]=1)[CH3:36]
Reactant: CCOCCN
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CCOCCNc1nccc(-c2sc(C(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)n1
Yield: 36 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.150 g, 0.286 mmol) and 2-ethoxyethylamine (0.5 mL, 4.77 mmol), the title compound was obtained (64 mg, 36% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.66-7.77 (m, 1H), 7.36-7.46 (m, 2H), 7.20-7.32 (m, 4H), 6.19 (s, 1H), 3.35-3.51 (m, 6H), 3.24-3.30 (m, 1H), 1.36 (d, J=6.9 Hz, 6H), 1.10 (q, J=6.7 Hz, 3H). MS (ESI): 578.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[C:5]([N:7]1[CH2:12][CH2:11][C:10]([CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)([F:13])[CH2:9][CH2:8]1)=[O:6].[N-:30]=[N+:31]=[N-:32].[Na+].[N-]=[N+]=[N-].C([N+](CCCC)(CCCC)CCCC)CCC>CS(C)=O>[N:30]([CH2:14][C:10]1([F:13])[CH2:11][CH2:12][N:7]([C:5]([C:4]2[CH:26]=[CH:27][C:28]([F:29])=[C:2]([Cl:1])[CH:3]=2)=[O:6])[CH2:8][CH2:9]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2(F)CCN(C(=O)c3ccc(F)c(Cl)c3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1(F)CCN(C(=O)c2ccc(F)c(Cl)c2)CC1
Temperature: 110 °C

Procedure:
0.70 g of toluene-4-sulfonic acid 1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl-methyl ester (1.57 mmol), 0.308 g of sodium azide (4.70 mmol) and 0.20 g of tetrabutylammonium azide (0.70 mmol) are mixed in 3.50 ml of dimethyl sulfoxide. The mixture is heated at 110° C. under a nitrogen atmosphere for 20 hours. The reaction mixture is poured into ice-cold water and then extracted with ethyl acetate. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a neutral alumina column (eluent: hexane/ethyl acetate; 70:30). 0.313 g of a yellow oil is obtained.
Reaction SMILES: N(=C([C:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([C:20](=[O:24])[CH2:21]2)[C@:17]2([CH3:18])[C@H:12]([CH2:13][CH:14]=[CH:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH:6]=1)C)O.P(Cl)(Cl)(Cl)=[O:26].Cl>N1C=CC=CC=1.O>[CH3:23][C@:22]12[CH2:21][C:20](=[O:24])[C@H:19]3[C@@H:9]([CH2:10][CH2:11][C@@H:16]4[C@:17]3([CH3:18])[CH2:12][CH:13]=[CH:14][CH2:15]4)[C@@H:5]1[CH2:6][CH2:7][C:8]2=[O:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=NO)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 60 h

Procedure:
A solution of 20-oximino-5α-pregna-2,16-diene-11-one (60 g) in anhydrous pyridine (250 ml) was treated with 225 ml of a solution prepared from phosphorus oxychloride (55 ml) in anhydrous pyridine (250 ml) whilst maintaining the reaction temperature at `5° during addition of the reagent. The reaction mixture was then added to a solution of concentrated HCl (350 ml) in water (3 l). This mixture was stirred for 60 hours before collecting the precipitate by filtration. The precipitate was washed with water, dissolved in hot industrial methylated spirits and treated with 2 N HCl (50 ml) at room temperature. After one hour, the reaction mixture was diluted with water and the precipitate obtained was collected by filtration, washed with water and dried. (38.4 g). Crystallisation from methanol afforded the title compound, m.p. 188°-192°, [α]D +207°.
Reaction SMILES: [Na].[Cl:2][CH2:3][C:4]#[N:5].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]([OH:18])=O)[CH2:12][CH2:11][CH2:10]2>CO>[Cl:2][CH2:3][C:4]1[NH:5][C:16](=[O:18])[C:15]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][C:13]=3[CH:14]=2)[N:6]=1
Reactant: Nc1cc2c(cc1C(=O)O)CCC2
Reactant: N#CCCl
Agent: [Na]
Solvent: CO
Product: O=c1[nH]c(CCl)nc2cc3c(cc12)CCC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Anhydrous methanol (36 ml) was added into a 250 ml round-bottomed flask that contained sodium (0.081 g) under argon. To this stirred solution chloroacetonitrile (1.56 g, 20.7 mmol) was added and stirring was continued for 30 min at room temperature under argon. 5-Amino-6-carboxyindane (European Patent Application 0602851A1; 3.19 g, 18.0 mmol) was then added and the reaction mixture was diluted with more methanol (42 ml). After the reaction mixture being stirred for 1 hour at room temperature, more anhydrous methanol (25 ml) was added and stirring was continued for 1 hour at room temperature and then for a further 1 hour at 80° C. under argon. The reaction mixture was then allowed to cool to room temperature; the white precipitate was collected by filtration, washed with methanol, water and dried in vacuo over P2O5 (3.15 g, 75%), mp 270-272° C.; 1H-NMR (DMSO-d6) 2.07 (m, 2H, 7-CH2), 2.98 (m, 4H, 6-CH2 and 8-CH2), 4.52 (s, 2H, 2-CH2), 7.50 (s, 1H, 9-H), 7.93 (s, 1H, 5-H), 12.37, (s, 1H, N3—H). MS (FAB, m/z) 235 (M+H)+;
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[N:16]=[C:15]([C:25]([F:28])([F:27])[F:26])[CH:14]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>CC(O)=O>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:31]=[CH:35][CH:34]=[CH:33]4)=[CH:20][CH:19]=3)[N:16]=[C:15]([C:25]([F:26])([F:28])[F:27])[CH:14]=2)=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(N)cc2)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(-n3cccc3)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A mixture of 2-{4-[1-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate 165.6 mg and 2,5-dimethoxytetrahydrofuran 112 mg in AcOH 3 ml was stirred at 50° C. for 3 hours. 2,5-Dimethoxytetrahydrofuran 0.22 ml was added and the mixture was stirred at 50° C. for 2 hours. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=20%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 2-{4-[1-[4-(1H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate 136.1 mg as an oil.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:3]=1[CH:4]=[O:5].C[C:15](=[O:19])[O:16]CC>>[F:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:3]=1[CH:4]([OH:5])[C:15]([OH:19])=[O:16]
Reactant: CCOC(C)=O
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Product: O=C(O)C(O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
The 2,3,4,5,6-pentafluorobenzaldehyde (49.4 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 52.3 g. (86.0). EA, MS(FD).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=2[C:18](O)=[S:19])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[C:28]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][C:16]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=2[C:18]([NH:26][C:27]2[C:28]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=3)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=2)=[S:19])[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(C(O)=S)c(O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1

Procedure:
Using a procedure analogous to Example 1-G, 2-(cis-4-t-butoxycarbonylaminocyclohexyloxy)-4-methylthiobenzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a white solid (2.68 g, 85%).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C=CC=CC=1.[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43](Cl)=[O:44])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C([O-])(O)=O.[Na+].CCOC(C)=O>CCOC(C)=O>[CH2:6]([O:5][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:43]([C:40]1[CH:39]=[CH:38][C:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=2)=[CH:42][CH:41]=1)=[O:44])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCOP(=O)(OCC)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3ccccc3P(=O)(OCC)OCC)cc2)cc1
Reaction time: 0.42 h

Procedure:
At rt, to a solution of (2-Amino-phenyl)-phosphonic acid diethyl ester in EtOAc are added 10 equivaltents of pyridine followed by 1 equivalent of 4′-octyloxy-biphenyl-4-carbonylchloride (VAW132) and the mixture obtained is stirred for ca. 25 minutes. The mixture obtained is subjected to an aqueous work-up (NaHCO3/EtOAc), the organic phase obtained is dried, solvent is evaporated and the evaporation residue is subjected to column chromatography. {2-[(4′-Octyloxy-biphenyl-4-carbonyl)-amino]-phenyl}-phosphonic acid diethyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(Cl)c1
Yield: 42.1 %

Procedure:
Using 0.16 g of 3-chlorobenzyl chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.12 g of 2-(3-chlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (82)).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[N+:25]([O-])=O)[CH:10]=1>ClCCl.CO.[Pd]>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:25])[CH:10]=1
Reactant: CC(C)Oc1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)Oc1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-isopropoxy-2-nitrophenyl)isonicotinamide (270 mg, 0.53 mmol, 1.00 equiv, 90%) in dichloromethane/methanol (3/6 mL). The solution was treated with Pd/C (270 mg), and stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum to yield 230 mg (91%) of product as a brown oil.