Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCO.[ClH:30]>[Fe].O>[ClH:30].[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([S:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([OH:1])[CH:7]=3)=[CH:14][CH:13]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(Sc2ccnc(O)c2)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)Nc2ccc(Sc3ccnc(O)c3)cc2)cc1
Reaction time: 8 h

Procedure:
Nitro compound 14 (0.48 g, 1.18 mmol) was suspended in 2:1 EtOH:H2O (100 mL) and the resulting suspension brought to reflux. To this mixture was sequentially added Fe dust (0.30 g, 9.59 mmol) and c.HCl (2 mL), and the resulting suspension refluxed for 15 min. TLC and LCMS analysis at this time showed that the reaction was incomplete, thus further quantities of Fe dust (0.80 g, 14.29 mmol) and c.HCl (10 mL) were added, and the mixture refluxed for a further 50 min. After this time, the reaction was complete, and thus the reaction mixture was filtered hot through a pad of Celite, and solvent was removed under reduced pressure. The residue was dried via two MeOH-azeotrope cycles, and then re-dissolved in MeOH and stirred overnight with Celite and activated charcoal. The resulting slurry was filtered through a pad of Celite, and solvent was removed under reduced pressure. The residue was re-dissolved in MeOH and adsorbed onto a quantity of silica gel, and the resulting silica adsorbate was purified by column chromatography on silica gel, eluting with 1%→20% MeOH:CH2Cl2 (with 0.5% aq.NH3), to afford crude 15. This material was purified further by re-precipitation from MeOH:methanolic HCl:EtOAc, to afford amine 15 as an amorphous cream solid (15 mg, 3%—presumably much material lost by adsorption to activated charcoal; latter was extracted several times, to little avail); 1H NMR [(CD3)2SO]: δ 11.40 (v v br s, 1H, quinolinyl-N+—H), 10.08 (s, 1H, ArH), 7.94 (ddd, J=9.40, 4.51, 2.59 Hz, 2H, ArH), 7.78 (d, J=8.67 Hz, 2H, ArH), 7.52 (ddd, J=9.40, 4.49, 2.61 Hz, 2H, ArH), 7.27 (d, J=6.95 Hz, 1H, ArH), 6.71 (d, J=8.52 Hz, 2H, ArH), 5.96 (dd, J=6.96, 1.93 Hz, 1H, ArH) [ArOH & ArNH2 not visible]; LCMS (APCl+): 338 (100%), 423 (60%), 169 (40%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:26][CH2:27][CH2:28][N:29]([CH3:52])[CH2:30][CH2:31][C@:32]3([O:46][C:47](=[O:51])[CH:48]([CH3:50])[CH3:49])[CH2:37][C@H:36]4[CH2:38][CH2:39][C@@H:33]3[CH:34]=[C:35]4[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:10](COCC[Si](C)(C)C)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl>[C:12]1([C:11]2[N:10]=[C:9]([CH2:26][CH2:27][CH2:28][N:29]([CH3:52])[CH2:30][CH2:31][C@:32]3([O:46][C:47](=[O:51])[CH:48]([CH3:50])[CH3:49])[CH2:37][C@H:36]4[CH2:38][CH2:39][C@@H:33]3[CH:34]=[C:35]4[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc(-c3ccccc3)c(-c3ccccc3)n2COCC[Si](C)(C)C)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Yield: 57 %

Procedure:
To a solution of 30 mg of rac-isobutyric acid (1R*,2R*,4R*)-2-[2-({3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propyl}-methyl-amino)-ethyl]-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester in 0.5 mL of anh. THF was added dropwise 0.2 mL of a 1M solution of TBAF in THF. The reaction mixture was refluxed for 6 h, diluted with DCM and washed with sat.-NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using EtOAc/MeOH/NEt3 from 100/0/1 to 90/10/1 as eluant to yield 14 mg of rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(4,5-diphenyl-1H-imidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as a yellowish solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[N:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)[O:13][N:12]=3)[CH:8]=2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=1)[CH2:17][CH2:16][C:14]1[O:13][N:12]=[C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)[N:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1nc(-c2ccc3c(c2)CC(=O)N3)no1)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CCc1nc(-c2ccc3c(c2)CC(=O)N3)no1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
tert-Butyl(R)-4-(3-(2-oxoindolin-5-yl)-1,2,4-oxadiazol-5-yl)-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (200 mg, 0.37 mmol) was dissolved in 5.0 mL anhydrous DCM, and 5.0 mL TFA was added. After 30 minutes stirring at room temperature, the solvent was evaporated and the residue was taken up in 100 mL EtOAc. To the resulting solution was added 50 mL of saturated aqueous sodium bicarbonate and 30 mL 5% aqueous sodium carbonate. The organic layer was washed with brine and dried over sodium sulfate to afford the product as a white solid (130 mg, 81%). MS (API-ES) m/z (%): 417.1 (100%, M++H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[O:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:21][CH2:22][CH2:23]CCC.C([Li])CCC.[F:32][C:33]1[CH:34]=[C:35](Br)[CH:36]=[CH:37][C:38]=1[Cl:39]>C1COCC1.[Cl-].[Zn+2].[Cl-].O>[CH2:21]([CH:18]1[CH2:17][O:16][CH:15]([CH:12]2[CH2:13][CH2:14][CH:9]([C:4]3[CH:5]=[C:6]([F:8])[C:7]([C:35]4[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([F:32])[CH:34]=4)=[C:2]([F:1])[CH:3]=3)[CH2:10][CH2:11]2)[O:20][CH2:19]1)[CH2:22][CH3:23]
Reactant: CCCCCC
Reactant: Fc1cc(Br)ccc1Cl
Reactant: Fc1cc(F)cc(C2CCC(C3OCCCO3)CC2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1COC(C2CCC(c3cc(F)c(-c4ccc(Cl)c(F)c4)c(F)c3)CC2)OC1
Temperature: -65 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
The above 5-propyl-2-(4-(3,5-difluorophenyl)cyclohexyl-1,3-dioxane 1.3 g (4.0 mmol) was dissolved in THF 10 ml, and cooled to −65° C. under a nitrogen atmosphere. To this solution, 1.68 M hexane solution 3.0 ml (5.0 mmol) of n-butyllithium was added dropwise keeping the liquid temperature below −55° C., and the mixture was stirred for one hour at the same temperature. Then, to the reactant, 0.5 M THF solution 10 ml (5.0 mmol) of zinc chloride was added dropwise keeping the liquid temperature below −50° C., and the mixture was heated to room temperature and stirred for 30 minutes. Tetrakistriphenylphosphin paradium 0.5 g and 3-fluoro-4-chlorobromobenzene 1.1 g (5.3 mmol) were added to the solution, and the mixture was refluxed with heating for 3 hours. Water 30 ml was added to the resulting reactant, and the product was extracted with toluene. The extract was washed with 3N-hydrochloric acid, a saturated bicarbonate aqueous solution and then a saturated sodium chloride aqueous solution, and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene), and recrystallized twice from a mixed solvent of heptane/ethyl acetate=1/1 to obtain 5-propyl-2-(4-(4-(3-fluoro-4-chlorophenyl)-3,5-difluorophenyl) cyclohexyl)-1,3-dioxane 1.7 g (3.8 mmol). The yield was 95.0% from 5-propyl-2-(4-(3,5-difluorophenyl)ethyl)-1,3-dioxane.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>CC(O)C>[ClH:1].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[C:3]3[S:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(OCc2cccs2)cc1
Reactant: Clc1ncnc2ccsc12
Solvent: CC(C)O
Product: Cl
Product: c1csc(COc2ccc(Nc3ncnc4ccsc34)cc2)c1
Yield: 61 %

Procedure:
4-Chlorothieno[3,2-d]pyrimidine (0.102 g, 0.60 mmol) and 4-(2-thienylmethoxy)-aniline (prepared according to the published method: WO 96/09294) (0.135 g, 0.66 mmol) were reacted in 2-propanol (5 ml) for 2 hours, according to Procedure A. The product was obtained as a grey-green solid (0.138 g, 61%) with m.p. 181-182° C.; (Found: C, 53.64; H, 3.61; N, 11.04. C17H13N3OS2.HCl.0.25H2O requires: C, 53.68; H, 3.84; N, 11.05%); δH [2H6]-DMSO 11.28 (1H, br s, NH), 8.75 (1H, s, 2-H), 8.45 (1H, d, J 7, 6 H or 7 H) 7.45-7.68 (4H, m, 6H or 7H, 2′-H, 6′-H, 5″-H), 6.95-7.28 (4H, m, 3′-H, 5′-H, 3″-H, 4″-H), 5.32 (2H, s, CH2); m/z 339 (M+).
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:10][C:11]=1[NH2:12])(=O)C.[OH-].[K+].O>C(O)C>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)=[CH:7][C:6]=1[CH2:5][NH2:4]
Reactant: CC(=O)NCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(CN)c2)CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
To a solution of compound 16 (0.70 g, 2 mmol) in ethanol (20 mL) was added 4M solution of KOH in H2O (4 mL, 16 mmol) and the mixture was stirred at 90° C. for 12 h. The mixture was concentrated under reduced pressure to get a brown oil material, which was resolved over silica column eluting with CH2Cl2:MeOH (95:5) and then changing to (90:10) to get compound 17 as light brown thick oil (0.51 g, 84%). IR (KBr) νmax. cm−1: 3421, 3411 (NH), 3053 (Ar—H), 2936 (Alph-H), 1697 (C═O), 1606, 1578 (C═C), 1244 (C—N), 1166 (C—O). 1H NMR (500 MHz, CDCl3) δ=1.47 (s, 9H, (C(CH3)3), 3.10 (br. s, 4H, 2CH2), 3.22 (br. s, 4H, 2CH2), 4.08 (s, 2H, CH2), 4.58 (br. s, 2H, NH2), 5.18 (br. s, 2H, NH2), 6.68 (dd, 1H, J=2.3, 9.3 Hz, H-6), 6.73 (br. s, 1H, H-2), 6.81 (d, 1H, J=9.2 Hz, H-5). 13C NMR (125.7 MHz, CDCl3) δ=28.05 (C(CH3)3), 42.43 (CH2), 45.26 (CH2), 50.54 (CH2), 79.75 (C(CH3)3), 112.01 (aromatic-C), 112.08 (aromatic-C), 117.00 (aromatic-C), 130.28 (aromatic-C), 134.08 (aromatic-C), 143.08 (aromatic-C), 154.70 (CO). Calculated (%) for C16H26N4O2 (306.21); C, 62.72; H, 8.55; N, 18.29. found (%); C, 62.66; H, 8.62; N, 18.20.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[Cu](C#N)[C:15]#[N:16].CN1CCCC1=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:15]#[N:16])[CH:7]=1)[CH3:2]
Reactant: N#C[Cu]C#N
Reactant: CCOC(=O)Cc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1cccc(C#N)c1
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of (3-bromo-phenyl)-acetic Acid ethyl ester (9.15 g, 37.6 mmol), copper cyanide (5.06 g, 56.5 mmol), and 1-methyl-2-pyrrolidinone (80 mL) was placed into an oil bath heated at 120° C. behind a protective shield. The reaction was heated to 200° C. for 1 h and additional copper cyanide (spatula tip) was added. After heating for an additional 0.5 h, the reaction was cooled to room temperature. The reaction was diluted with EtOAc and the organic solution was washed with water/ammonium hydroxide solution (2:1 v/v) until the aqueous solution was no longer blue. The organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc) provided (3-cyano-phenyl)-acetic Acid ethyl ester (6.31 g) as a clear oil which solidified on standing. 1H NMR (400 MHz, CDCl3) δ 7.57-7.50 (m, 3H), 7.42 (m, 1H), 4.15 (q, 2H), 3.63 (s, 2H), 1.24 (t, 3H).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH3:25][CH:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:25][CH:26]([CH3:27])[C:29]([F:32])([F:31])[F:30])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC(C=O)C(F)(F)F
Agent: Cl
Product: CC(CN1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1)C(F)(F)F

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively alkylated with rac-2-methyl-trifluoropropionaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3,3,3-trifluoro-2-methyl-propyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 464.1 [M+H]+.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]([F:23])([F:22])[C:8]1[CH:13]=[C:12]([CH2:14][Br:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH2:20]Br>CO>[Br-:15].[Br-:15].[F:6][C:7]([F:23])([F:22])[C:8]1[CH:13]=[C:12]([CH2:14][S+:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH2:20][S+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(CBr)c(C(F)(F)F)cc1CBr
Reactant: C1CCSC1
Solvent: CO
Product: FC(F)(F)c1cc(C[S+]2CCCC2)c(C(F)(F)F)cc1C[S+]1CCCC1
Product: [Br-]
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Tetrahydrothiophene (0.27 mL, 3 mmol) was added to a suspension of compound 24 (200 mg, 0.5 mmol) in dry methanol (5 mL). The solid was dissolved to form a clear solution within 10 min. This solution was filtered via 0.45 μm membrane filter and then heated to 50° C. with stirring for 24 h. After cooling down to room temperature, the solvent was completely removed in vacuo and cold acetone (10 mL) was added to the residue. The precipitate was then filtered and dried to give compound 217a as a colorless, hygroscopic solid (192 mg, 67%): 1H NMR (300 MHz, D2O): 8.17 (2H, s), 4.76 (4H, s), 3.52-3.62 (8H, m), 2.34-2.47 (8H, m); 19F NMR (282 MHz, D2O): −60.2; HR-MS (EI) calcd. for C18H22F6S2Br2 (M+): 573.94, found ([M-Br]+): 495.04.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](O)=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C(O)C(Sc1ccc(Cl)cc1)c1ccccc1
Solvent: O=S(Cl)Cl
Product: Clc1ccc2sc(-c3ccccc3)c(N3CCCCC3)c2c1

Procedure:
20 g (72 mmole) of α-(4-chlorophenylthio)-phenylacetic acid and 20 milliliters (280 mmole) of SOCl2 are refluxed for 3 hours. After the excess SOCl2 has been removed, the crude acid chloride is dissolved in 100 milliliters of dioxan and, with stirring the cooling, 21.2 milliliters (290 mmole) of piperidine are added dropwise. After dilution in water, the mixture is extracted with CH2Cl2. By evaporating the organic phase dried over Na2SO4, 22.6 g (91% theory) of the piperidinium salt of α-(4-chlorophenylthio)-phenylacetic acid are obtained: colourless rods, mp 125°-126° (benzene/petroleum ether).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].Cl[C:39](OC1C=CC([N+]([O-])=O)=CC=1)=[O:40].[CH3:51][P:52]([C:55]1[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=1)[NH2:58])([CH3:54])=[O:53].CCN(C(C)C)C(C)C>O1CCCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:39]([NH:58][C:57]4[CH:59]=[CH:60][CH:61]=[C:55]([P:52]([CH3:51])([CH3:54])=[O:53])[CH:56]=4)=[O:40])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CP(C)(=O)c1cccc(N)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cccc(P(C)(C)=O)c5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of compound 126 (schemes 6 or 9) (200 mg, 0.381 mmol) in dry tetrahydrofuran (8 mL) under nitrogen at −20° C. was added 4-nitrophenyl chloroformate (115 mg, 0.572 mmol). The reaction mixture was stirred at −20° C. for 2 h. A solution of 3-(dimethylphosphoryl)aniline 287 (97 mg, 0.57 mmol) and N,N′-diisopropylethylamine (0.200 mL, 1.14 mmol) in a mixture of dry tetrahydrofuran (2 mL) and dry N,N′-dimethylformamide (2 mL) were added at −20° C., the reaction mixture was allowed to warm to room temperature slowly, and the stirring was continued for an additional 16 h. The solvent was removed under reduced pressure; the residue was diluted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate and concentrated. Purification via Biotage (linear gradient 0-20%, methanol/dichloromethane; 25M column) afforded compound 288 (230 mg, 0.32 mmol, 84%). MS (m/z): 720.4 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(OCc2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(OCc2ccccc2)c2ccccc12
Yield: 82.9 %

Procedure:
A mixture of 2 g (8 mmol) of 4-benzyloxy-naphthalen-1-ol [Journal of Medicinal Chemistry (1985), 28(6), 822-41, of 2.67 g (16 mmol) of ethyl bromoacetate and of 3.12 g (9.6 mmol) of cesium carbonate in 30 ml of acetonitrile was stirred at 60° C. for 3 hours. Subsequently, the reaction mixture was evaporated to dryness and the residue was partitioned between water and tert.-butyl methyl ether. The organic phase was separated, washed with water and brine, dried over anhydrous sodium sulfate and finally evaporated. 2.23 g of the title compound were obtained as white crystals after crystallization from n-heptane.
Reaction SMILES: [CH2:1]([NH:4][C:5]#[N:6])[CH:2]=[CH2:3].[Cl:7][C:8](=[CH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:23]([Cl:24])=[C:22]([O:25][CH:26]([F:28])[F:27])[N:21]([CH3:29])[N:20]=2)[C:16]([Cl:30])=[CH:15][C:14]=1[Cl:31])[C:9](Cl)=[O:10].[O:32]1CCCC1>>[CH2:1]([N:4]([C:5]([NH2:6])=[O:32])[C:9](=[O:10])[C:8]([Cl:7])=[CH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:23]([Cl:24])=[C:22]([O:25][CH:26]([F:28])[F:27])[N:21]([CH3:29])[N:20]=2)[C:16]([Cl:30])=[CH:15][C:14]=1[Cl:31])[CH:2]=[CH2:3]
Reactant: C1CCOC1
Reactant: C=CCNC#N
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Product: C=CCN(C(N)=O)C(=O)C(Cl)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Temperature: 55 °C
Reaction time: 5 h

Procedure:
0.36 g (4.4 mmol) of allylcyanamide were added to a suspension of 2 g (4.4 mmol) of 2-chloro-3-(2,4-dichloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)phenyl)Propenoyl chloride and 0.8 g (5.8 mmol) of potassium carbonate(ground) in 50 ml of tetrahydrofuran. The reaction mixture was stirred at 50 to 60° C. for 5 hours and then concentrated. The residue was taken up in ethyl acetate, after which the organic phase was washed with water, dried over magnesium sulfate and concentrated. The crude product was purified by means of column chromatography on silica gel (eluent: ethyl acetate) followed by crystallization from diisopropyl ether. Yield: 0.2 g.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([O:28]C)=[O:27])[CH:24]=3)[C:19]([S:30]([CH3:32])=[O:31])=[CH:18]2)=[N:15][CH:16]=1>O.C1COCC1.O>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=3)[C:19]([S:30]([CH3:32])=[O:31])=[CH:18]2)=[N:15][CH:16]=1
Reactant: COC(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (0.34 g, 8.05 mmol) in water (2 mL) was added to an ice-cooled suspension of methyl ester 51d) (2.2 g, 5.37 mmol) in THF/water (1:1; 40 mL) and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum and the remnant was dissolved in water (20 mL) and washed with ethyl acetate (2×20 mL). The aqueous phase was acidified with sodium hydrogen sulfate and extracted with dichloromethane (2×50 mL). The organic layers were dried over sodium sulfate and evaporated. White solid. Yield: 1.8 g (85% of theory). HPLC-MS (method 5): Rt=2.6 min; m/z [M+H]+=396
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:16]=1[NH2:17].O>CC(C)=O>[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:16]=1[NH:17][C:2]([NH:3][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:1]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Reactant: Nc1c(Cl)cccc1Cl
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(=S)Nc1c(Cl)cccc1Cl)c1ccccc1
Temperature: 0 °C

Procedure:
To 51.8 g. (0.68 mole) of ammonium thiocyanate in 300 ml acetone is added 86.8 g (0.62 mole) of benzoyl chloride. The reaction mixture is refluxed for about 5 min. and then 100 g (0.62 mole) of 2,6-dichloroaniline in 200 ml acetone is added at a rate to maintain reflux. The mixture is refluxed for 11/2 hours, cooled, poured into 11/2 liters of ice and water, filtered to obtain 1-(2,6-dichlorophenyl)-3-benzoylthiourea.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:18](I)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1)#[CH:23]>>[F:1][C:2]1[C:3]2[N:4]([C:18]([C:23]#[C:22][C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Fc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Product: Nc1ccc(C#Cc2cnc3c(F)cc(-c4ccc(C(F)(F)F)cc4)cn23)cn1

Procedure:
The title compound was prepared from 8-fluoro-3-iodo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.29 step 6) (350 mg, 0.85 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (122 mg, 0.85 mmol) according to general procedure II. Obtained as an off-white solid (130 mg, 38%). MS (ISP) 397.2 [(M+H)+]; mp 281-282° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(OC)nc2c1O
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1Cl

Procedure:
A mixture of ethyl 4-hydroxy-6-methoxy-1,5-naphthyridine-3-carboxylate (2.48 g) and phosphorus oxychloride (25 ml) was stirred and heated at 50°-55° C. for 30 minutes. The mixture was worked up as described in Example B1 to give ethyl 4-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate, m.p. 98°-100° C.