Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:34][C:20]3[N:21]=[CH:22][N:23]=[C:24]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=4)[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)C.O.[OH-].[Na+]>C1COCC1>[Cl:33][C:28]1[CH:27]=[C:26]([NH:25][C:24]2[C:19]3[CH:18]=[C:17]([C:14]4[CH:15]=[CH:16][C:11]([CH2:10][OH:9])=[CH:12][CH:13]=4)[NH:34][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CCOC(=O)c1ccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)cc1

Procedure:
570 mg (15 mmol) lithium aluminium hydride are suspended in 150 ml dry THF at RT. 4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid ethyl ester (1.23 g, 3 mmol) are added and the resulting mixture is heated to reflux for 1 h. The mixture is cooled in an ice bath and treated sequentially with water (0.57 ml), 15% sodium hydroxide solution (0.57 ml) and water (1.71 ml). The solid aluminum complex is removed by filtration (Hyflo Super Cel®; Fluka, Buchs, Switzerland), the filtrate dried over sodium sulfate and the solvent evaporated. The residue was suspended in water, filtered and dried to give the title compound; m.p. >300° C.; HPLC tR=9.14 min.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:2]([Cl:1])=[O:4])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCCCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 188.5 %

Procedure:
In a four necked round bottom flask, triphosgene (22.0 g, 74.2 mmol) was dissolved in toluene (325 mL) under argon. After cooling at 0° C., pyridine (19.2 mL, 237.5 mmol) was added dropwise during 1 h and the resulting suspension stirred for 1 h at 0° C. 5-phenylpentanol (25 mL, 148.4 mmol) was added drop wise in 30 min. After stirring at rt for 16 h the solid was filtered-off and the solvent removed under vacuum yielding the title compound (31.7 g, 94%), which was used in the next step without further purification. Rf=0.75 (Cy/AcOEt 8:2). FTIR (cm−1): 3087, 3063, 3027, 2936, 2859, 1778, 1744, 1604, 1496, 1455, 1382, 1260, 1146, 1031, 941, 835, 731, 696.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=O)OC(C)(C)C)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][CH3:17])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl(3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamate (59 mg, 0.187 mmol) from Step A was treated with lithium aluminum hydride (0.374 mmol) in tetrahydrofuran (0.5 mL). The reaction was stirred at room temperature for 1 hour and then heated to reflux for 2 hours. The reaction was cooled to room temperature and quenched with dropwise addition of saturated aqueous sodium sulfate (50 μL) to give a precipitate. The precipitate was washed with tetrahydrofuran, and then the solvent was removed to give (3aR,4S,6aS)-2-benzyl-N-methyloctahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.34-7.28 (m, 4H), 7.25-7.19 (m, 1H), 3.60-3.51 (m, 2H), 2.76 (q, J=5.6, 1H), 2.64 (d, J=15.7, 1H), 2.58-2.53 (m, 1H), 2.51-2.46 (m, 1H), 2.40-2.35 (m, 4H), 2.31-2.22 (m, 2H), 1.98-1.85 (m, 2H), 1.39 (dt, J=5.7, 10.6, 3H); MS (ESI+) m/z 231 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C@@H:27]([OH:33])[C@H:26]([O:34][C:35](=[O:37])[CH3:36])[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C:27](=[O:33])[C@H:26]([O:34][C:35](=[O:37])[CH3:36])[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](O)[C@H](OC(C)=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)[C@H](OC(C)=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1

Procedure:
Using the procedure described in Org. Syn., 1976, 55, 84, (3β,5α,11β,12α,25R)-3,12-di(acetoxy)-spirostan-11-ol was oxidized with chromium trioxide and pyridine in methylene chloride to give the title compound.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1Br)[C:8](=[O:11])[O:9][CH3:10].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][C:35]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O.CCCCCC>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[C:39]1[CH:38]=[C:37]([CH:40]([CH3:42])[CH3:41])[CH:36]=[CH:35][C:34]=1[O:33][CH3:32])[C:8](=[O:11])[O:9][CH3:10]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc([N+](=O)[O-])ccc1Br
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc([N+](=O)[O-])ccc1-c1cc(C(C)C)ccc1OC

Procedure:
To a mixture of Methyl [3,5-bis(trifluoromethyl)benzyl](2-bromo-5-nitrobenzyl)carbamate from Step D (0.39 g, 0.75 mmol), 2-methoxy-5-isopropylphenyl boronic acid (0.175 g, 0.90 mmol), and potassium carbonate (0.21 g, 1.50 mmol) in 4:1 acetone/water (10 ml), a catalytic amount of palladium acetate (10 mg) was added. The mixture was heated to and maintained at reflux for 2 h. TLC analysis (acetone/hexane=5:95) showed completion of the reaction. The acetone was removed under reduced pressure and the organic was extracted with methylene chloride (3×25 ml). The combined organic layers were washed with brine and dried over sodium sulfate. The title compound was obtained by flash column chromatography using 5:95 acetone/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 8.20 (m, 2H), 7.75 (s, 1H), 7.48 (m, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.29 (m, 1H), 6.93 (m, 2H), 4.25-4.60 (m, 4H), 3.80 (m, 3H), 3.69 (s, 3H), 2.89 (m, 1H), 1.20 (s, 6H). LC-MS (M+1) 585.4 (4.49 min).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[CH2:9]Br.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30].O>C(#N)C>[CH3:32][CH:31]([CH3:33])[CH:29]([N:30]1[CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[C:5]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[CH:4]=2)[CH2:9]1)[C:28]([O:27][CH3:26])=[O:34]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(CBr)c(CBr)c2)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1

Procedure:
The compound of example 671 (3 g, 7.79 mmol) was taken in acetonitrile and to the reaction mixture, potassium carbonate (3.25 g, 23.37 mmol) was added followed by the addition of valine methyl ester (1.56 g, 9.35 mmol). The reaction mixture was refluxed for about 16 h and water was added to quench the reaction. The aqueous mixture was extracted with ethyl acetate to obtain a crude material, which was purified using column chromatography (silicagel, 30% ethyl acetate in petroleum ether).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH:7]=1.[OH-].[NH4+:20]>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:20])[N:10]=2)[CH:7]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccnc(Cl)n1
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1nccc(Nc2cc(Br)ccc2[N+](=O)[O-])n1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To a solution of N-(5-bromo-2-nitrophenyl)-2-chloropyrimidin-4-amine (6 g, 18.21 mmol) in 2-propanol (70 mL), in a pressure vessel, was carefully added ammonium hydroxide solution (150 mL) at RT. The reaction vessel was sealed and stirred at 90° C. (at 4.5 bar pressure) for 20 hr. The reaction mixture was cooled to 0° C. The resulting precipitate was collected by vacuum filtration, washed with water and dried in the vacuum oven to afford the title compound as an orange solid: 1H NMR (250 MHz, DMSO) δ 6.17 (1H, d, J=5.63 Hz), 6.34 (2H, br. s.), 7.39 (1H, dd, J=8.83, 1.98 Hz), 7.89-7.99 (2H, m), 8.34 (1H, d, J=2.13 Hz), 9.62 (1H, s); LC-MS: m/z+309.9, 311.7 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]([CH3:16])[CH3:15].I[CH3:18].[H-].[Na+].[OH-].[Na+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[N:7]([CH3:18])[CH:6]=[C:5]2[CH:14]([CH3:16])[CH3:15]
Reactant: CI
Reactant: CC(C)c1c[nH]c2c(C(=O)O)cc(Br)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cn(C)c2c(C(=O)O)cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of 5-bromo-3-(1-methylethyl)-1H-indole-7-carboxylic acid (4.1 g, 14.53 mmol) in DMF (100 mL) at 0° C. was added iodomethane (3.6 mL, 57.6 mmol) followed by sodium hydride 60% dispersion in oil (1.4 g, 35.0 mmol) portionwise over 15 minutes. The reaction was allowed to warm to RT and stirred for 2 h. The reaction was recooled to 0° C., carefully quenched with water (5 mL), and evaporated to near dryness under vacuum. The residue was taken up in MeOH (50 mL) then treated with 6 N NaOH (10 mL, 60.0 mmol). The reaction was heated to 60° C. and stirred for 4 h. After cooling to RT the reaction was concentrated to near dryness, diluted with water, acidified with 6 N HCl (10 mL, 60 mmol), extracted with CH2Cl2, dried (Na2SO4), filtered, and evaporated to dryness to give the crude acid as a brown solid. Purification by silica gel chromatography (Analogix, SF40-120 g, 0 to 50% EtOAc in hexanes) gave material which was triturated with hexanes, filtered and dried under vacuum to give the product 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid (2.98 g, 10.06 mmol, 69.2% yield) as a white solid. MS (ES)+ m/e 296.3 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)(=[O:27])=[O:26])=[O:18])[C:13](O)=[O:14])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C1C[N:41]([P+](Br)(N2CCCC2)N2CCCC2)[CH2:40]C1.F[P-](F)(F)(F)(F)F.CN.C1COCC1>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)(=[O:26])=[O:27])=[O:18])[C:13](=[O:14])[NH:41][CH3:40])=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)O)cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.3 %

Procedure:
To a room temperature solution of (S)-3-(4-isopropoxy-phenyl)-2-{[(S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-propionic acid (319 mg, 0.588 mmol) (prepared according to the method described for the preparation of compound 17e), PyBroP (301 mg, 0.645 mmol), and methylene chloride (8 mL) was added methylamine (3.0 mL of a 2M THF solution) in one portion. The reaction mixture was shaken at room temperature in a sealed vessel for 2.5 h. The reaction mixture was then diluted with methylene chloride, washed with 0.5 N HCl and water successively, dried over MgSO4, filtered, and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate. Homogenous fractions with Rf=0.32 (silica gel, ethyl acetate) material were combined and concentrated to afford 197 mg (60%) of the title compound as a white foam. LC/MS: RT 3.38 min, Area % 100, m/e 556 (M+H). 1H NMR (400 MHz, d6-DMSO) δ8.01 d (J=8 Hz; Tyr NH), 7.99 brd (J=7.5 Hz; H-6 of ArSO2), 7.94 brs (H-2 of ArSO2), 7.84 q (J=4.5 Hz; CONHMe), 7.72 brd (J=8 Hz; H-4 of ArSO2), 7.59 dd (J=8, 7.5 Hz; H-5 of ArSO2), 7.11 m (2H, AA′-part of AA′MM′; H-2/H-6 of C6H4), 6.82 m (2H, MM′-part of AA′MM′; H-3/H-5 of C6H4), 4.56 brd (J=5 Hz; Pip H-2), 4.53 qq (J=6 Hz, 6; OiPr), 4.21 ddd (J=9, 8, 5.5 Hz; Tyr Ha), 3.65 dm (J=12.5; Pip H-6 eq), 3.17 ddd (J=13, 12.5, 3; Pip H-6ax), 2.84 dd (J=13.5, 5.5; Tyr Hb), 2.66 dd (J=13.5, 9; Tyr H′b), 2.53 d (3H, J=4.5; CONHMe), 1.95 brd (J=13.5; Pip H-3 eq), 1.49 dm (J=12.5 Hz; Pip H-Seq), 1.40 m (Pip H-4 eq), 1.36 m (Pip H-3ax), 1.21 d (3H, J=6 Hz; OiPr), 1.19 d (3H, J=6 Hz; OiPr), 1.16 m (Pip H-5ax), 1.06 m (Pip H-4ax).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].O>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:14][C:11]2[C:12]3[CH2:13][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH2:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)=[O:24])=[CH:18][C:17]=1[C:25]([F:26])([F:27])[F:28]
Reactant: CCOC1=CCc2cccc(N)c2C1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: O
Solvent: C1CCOC1
Product: CCOC1=CCc2cccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (0.16 g, 0.84mmol) in tetrahydrofuran (15 mL) was added 4-chloro-3-trifluoromethyl-phenylisocyanate (0.22 g, 1.0 mmol). The mixture was stirred at room temperature for 1.5 hours and was poured into water. The product was extracted with ethylacetate, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N-(4-chloro-3-trifluoromethyl-phenyl)-N′-(7-ethoxy-5,8-dihydro-naphthalen-1-yl)urea (0.31 g, 89% yield). Next, to a solution of N-(4-chloro-3-trifluoromethyl-phenyl)-N′-(7-ethoxy-5,8-dihydro-naphthalen 1-yl)-urea (0.21 g, 0.51 mmol) in tetrahydrofuran (20 mL) was added a solution of aqueous 1N hydrochloric acid (5 mL), and the mixture was stirred at 40° C. for 45 minutes. The mixture was neutralized with addition of 10% aqueous sodium bicarbonate solution, and extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N(4-chloro-3-tri-fluoromethyl-phenyl)-N′-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)urea (0.16 g, 85% yield). Next, to N-(4-chloro-3-trifluoromethyl-phenyl)-N′-7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)urea (0.07 g, 0.18 mmol) in methanol (10 mL) was added sodium borohydride (0.04 g, 0.09 mmol) at 0° C., and the mixture was stirred for 30 minutes. The mixture was poured into water, and the product was extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the obtained product was recrystalized from a mixture of ethylacetate/hexane (1/2) solution to give N-[4chloro-3-(trifluoromethyl)phenyl]-N′-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea (41 mg, 59% yield)
Reaction SMILES: Cl.C(O)C.[F:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[C:8]([F:18])[C:7]=1[CH3:19].S([O-])(O)(=O)=O.[Na+]>O.[Fe].C1C=CC=CC=1>[F:5][C:6]1[C:7]([CH3:19])=[C:8]([F:18])[C:9]([N+:15]([O-:17])=[O:16])=[CH:10][C:11]=1[NH2:12]
Reactant: Cc1c(F)c([N+](=O)[O-])cc([N+](=O)[O-])c1F
Agent: [Fe]
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: Cc1c(F)c(N)cc([N+](=O)[O-])c1F
Temperature: 50 °C
Yield: 62.9 %

Procedure:
To a suspension of iron powder (16.8 g, 100 mesh) in water (140 ml), with vigorous stirring at 50° C., was slowly added concentrated hydrochloric acid (3 ml). After hot ethanol (90 ml) was mixed, 2,6-difluoro-3,5-dinitrotoluene (21.8 g) was added portionwise to the suspension at 55° to 56° C. during 5 minutes. After stirring for 1.5 hours at 55° to 60° C., to the reacting mixture was added sodium hydrogensulfate (3.48 g) and stirred for further 30 minutes at the same temperature. To the reacting mixture was added benzene (100 ml), stirred for 10 minutes and insoluble materials were filtered off, and then the materials were washed with benzene. To the filtrate and washings were added water and active carbon, stirred sufficiently and filtered off. The organic layer was separated and the water layer was further extracted with benzene. The organic layer was combined, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (11.82 g) as pale brown crystals.
Reaction SMILES: [Li:1].C1C2C(=CC=CC=2)C=CC=1.Cl[P:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[C:23]=1[C:24](Cl)=[O:25]>O1CCCC1>[CH3:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[C:23]=1[C:24]([PH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:25].[Li:1]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: ClP(Cl)c1ccccc1
Agent: [Li]
Solvent: c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(=O)Pc2ccccc2)c(C)c1

Procedure:
Under argon and with the exclusion of moisture, 14.0 g of lithium (2.0 mol) are introduced into 250 ml of tetrahydrofuran at room temperature. Following the addition of 1.25 g of naphthalene, 44.8 g (0.25 mol) of dichlorophenylphosphine are added dropwise with stirring at 20–25° C. and, after stirring for 4 h, the black solution is filtered into a three-necked round flask through a frit (G2 porosity) with the exclusion of moisture and under argon as a protective gas. 47.2 g (0.258 mol) of 2,4,6-trimethylbenzoyl chloride are added dropwise at room temperature over the course of 30 minutes with stirring and cooling. Stirring for 2 hours gives the title compound as a red solution in tetrahydrofuran.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:29][NH2:30]>CO.CC(O)=O.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:30][CH3:29])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: CN
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reaction time: 3 h

Procedure:
To a solution of 5-fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 76.1., 0.60 g) in MeOH (5.0 ml), AcOH (0.92 ml), tetrahydrofuran (2.0 ml) and methyl amine (2 M in THF, 3.2 ml) was added portion wise Na(CN)BH3 (202 mg) and stirring was continued at 22° C. for 3 h. The mixture was evaporated and the residue partitioned between 1 N aqueous HCl and dichlormethane. The pH of the aqueous layer was adjusted to 11 using NaOH, extracted with dichloromethane, dried and evaporated to give 5-fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless oil. MS: 391.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].[H][H]>C(OCC)(=O)C.[Ni]>[NH2:9][C:4]1[C:3]([OH:12])=[C:2]([Br:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cc(Br)c1O
Yield: 99 %

Procedure:
A solution of 2-bromo-4-chloro-6-nitro-phenol (16.27 g, 64.4 mM) in ethyl acetate (160 ml) was hydrogenated, at room temperature, with Raney-nickel (6 g). After hydrogen uptake (approx. 4.8 1) was complete, the nickel was removed by filtration and the filtrate evaporated in-vacuo to give 14.19 g (99.0%) of the title compound which was suitable for the next step.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].S(OC)(O[CH3:15])(=O)=O.[OH-].[Na+]>>[CH:3]([O:8][CH3:15])([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1]
Reactant: COS(=O)(=O)OC
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: COC(C(F)(F)F)C(F)(F)F

Procedure:
Chain transfer agent of structure (1) may also be obtained by reaction of a fluorine containing alcohol R2OH with an alkylating agent of structure R1—L. In one example, reaction of 1,1,1,3,3,3-hexafluoro-2-propanol with dimethyl sulfate in the presence of aqueous sodium hydroxide affords a partially fluorinated ether with the structure (CF3)2CHOCH3, as disclosed in U.S. Pat. No. 3,346,448.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:16])[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6]1)=[O:4].[H-].[Na+].[CH3:19]I>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C@:5]1([CH3:16])[C:10](=[O:11])[N:9]([CH3:19])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6]1)=[O:4]
Reactant: COC(=O)C1(C)Oc2ccccc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@]1(C)Oc2ccccc2N(C)C1=O
Yield: 70.5 %

Procedure:
To a solution of (+)-methyl-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-2-carboxylate (0.9 g, 4.1 mmoles) in anhydrous toluene (20 ml), NaH (0.12 g, 5.1 mmoles) and methyl iodide (0.87 g, 6.1 mmoles) were added with stirring and the mixture was heated at reflux temperature for 2 hours. After the completion of the reaction, the toluene solution was washed with water (2×20 ml), 0.1M HCl (2×20 ml) and saturated NaCl solution (20 ml). The solution was dried over MgSO4 and the solvent was evaporated. Thus there were obtained 0.68 g of the title product, which was recrystallized from a mixture of hexane and diethyl ether. The title product was in the form of white crystals, m.p. 76°-78° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C@@H:7]([NH:10]S(C(C)(C)C)=O)[CH2:8][CH3:9])[O:4][N:3]=1.[ClH:17].O1CCOCC1>CO>[ClH:17].[Br:1][C:2]1[CH:6]=[C:5]([C@@H:7]([NH2:10])[CH2:8][CH3:9])[O:4][N:3]=1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1cc(Br)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](N)c1cc(Br)no1
Reaction time: 2.5 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(3-bromo-isoxazol-5-yl)-propyl]-amide (17.5 mg, 0.0566 mmol) in MeOH (1 mL) was added a 4 M solution of HCl in dioxane (0.70 mL, 0.28 mmol) dropwise. After 2.5 hours, the mixture was concentrated in vacuo to afford the title compound which was used with out purification. MS m/z 188.24 (M-53), 190.20 (M+2-53).