Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:45])[CH2:14][CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([N:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[S:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])=[O:22])[C:16](=[O:19])[CH2:17][F:18])(C)(C)C>C(Cl)Cl>[F:18][CH2:17][C:16](=[O:19])[CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([N:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[S:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])=[O:22])[CH2:14][C:13]([OH:45])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a stirred ice cold solution of [3S/R, (2S)]-5-fluoro-4-oxo-3-{[1-(phenothiazine-10-carbonyl)piperidine-2-carbonyl]amino}-pentanoic acid tert-butyl ester (130 mg, 0.24 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0° C. for 0.5 h then at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and then the residue was dissolved in dry DCM. This process was repeated several times in order to remove excess trifluoroacetic acid. The gum was lyophilized twice from HPLC grade water to afford the title compound as a white powder (77 mg, 66%): IR (solid) 1670, 1716, 1782 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.96-0.99 (1H, m), 1.23-1.26 (2H, m), 1.42-1.44 (1H, m), 1.60 (1H, m), 1.91-1.98 (1H, m), 2.51-2.89 (2H, m), 3.11-3.22 (1H, m), 3.57-3.60 (1H, m), 4.30-4.72 and 5.05-5.29 (4H, 2 m), 7.11-7.17 (2H, m), 7.24-7.30 (2H, m), 7.34-7.38 (2H, m), 7.57-7.63 (2H, m), 8.07-8.61 (1H, m); 13C NMR (100 MHz, DMSO) δ (DMSO+TFA) 18.8/18.9 (CH2), 22.2/22.3 (CH2), 25.8/26.1 (CH2), 31.5/33.2 (CH2), 43.2 (CH2), 50.6/51.1 (CH), 54.4/54.5 (CH), 82.8/82.9 (2d, J 178.6/178.1, CH2F), 119.9/120.0 (CH), 120.4/120.5 (CH), 124.0/124.1 m(CH), 125.9/126.0 (C), 126.4/126.5 (CH), 139.6/139.7 (C), 156.0/156.4 (CO), 170.3 (CO), 170.7/170.8 (CO), 202.2/202.3 (2d, J 14.6/15.1, CO).; 19F (376 MHz, DMSO) δ chemical shift (multiplicity, relative intensity) −226.7 (t, 3), −226.9 (t, 3), −230.4 (t, 1), −231.2 (t, 1), −232.7 (t, 10), −233.0 (t, 10).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C:28](=[O:33])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(C1(C)CCN(C2N3C=C(C(OCC)=O)N=C3C=C(C)C=2[C@H](O)C(OC)=O)CC1)CC=C>>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([OH:33])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCCC1(C)CCN(c2c([C@H](O)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](O)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Yield: 80 %

Procedure:
Prepared from methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-oxoacetate in 80% yield following the same procedure as (S)-ethyl 5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(1-hydroxy-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 8.01 (s, 1H), 7.96 (br. s., 1H), 7.51-7.31 (m, 3H), 6.24-6.09 (m, 1H), 5.58-5.50 (m, 2H), 5.46-5.40 (m, 1H), 4.83-4.72 (m, 1H), 4.02 (d, J=5.0 Hz, 2H), 3.90 (t, J=11.8 Hz, 2H), 3.79 (s, 3H), 2.91 (d, J=8.0 Hz, 1H), 2.66 (d, J=10.8 Hz, 1H), 2.49 (s, 3H), 1.99 (t, J=11.8 Hz, 2H), 1.82 (qd, J=12.9, 4.8 Hz, 2H), 1.34 (s, 3H); LCMS (ESI, M+1): 528.25.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:37])[N:22]([CH3:36])[C:23](S(C)(=O)=O)=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:16][CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:37])[N:22]([CH3:36])[C:23]([O:12][CH2:11][CH2:10][CH2:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:18][CH:19]=1
Reactant: Cn1c(S(C)(=O)=O)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reactant: OCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(OCCCc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% oily suspension, 111 mg, 2.79 mmol) was added to a stirred solution of 3-phenylpropanol (387 mg, 2.85 mmol) in tetrahydrofuran (1 ml). After gas evolution ceased, 5-(4-fluorophenyl)-3-methyl-2-methylsulfonyl-6-(4-pyridyl)-4(3H)-pyrimidinone (100 mg, 0.279 mmol) was added and the mixture was heated at 60μ C. for 30 min. The reaction mixture was partitioned between dichloromethane and water. The organic solution was washed with brine, dried and evaporated. Column chromatography on silica gel (hexane-ethyl acetate=2:1) provided the title compound. MS (m/z): 416.1 (M+H)+; C25H22FN3O2 requir. 415.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[O:20])=[C:17]([O:35][CH3:36])[CH:16]=2)[N:10]=1.[C:37]([Cu])#[N:38]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:37]#[N:38])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[O:20])=[C:17]([O:35][CH3:36])[CH:16]=2)[N:10]=1
Reactant: N#C[Cu]
Reactant: COc1cc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: COc1cc(-n2nc(-c3c(Cl)cccc3C#N)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by following the procedure as described for Example-62 by using 4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methoxybenzamide (Intermediate-43, 0.130 g, 0.21 mmol), DMF (4 mL) and CuCN (0.020 g, 0.23 mmol) to afford 0.030 g of crude product which was further purified by column chromatography in basic alumina eluting with 50% methanol:DCM and few drops of 10% ammonia to afford 0.030 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 3.94 (s, 3H), 7.52 (t, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.81 (m, 3H), 8.05-8.12 (m, 3H), 8.26 (s, 1H), 10.40 (s, 1H), 13.01 (br s, 1H); MS (m/z): 532.12 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Al+3].[Cl-].[Cl-].[Cl-].Br[C:14]([CH3:19])([CH3:18])[C:15](Br)=[O:16].Br.Cl>ClC1C=CC=CC=1>[CH3:18][CH:14]1[CH2:19][C:4]2[C:3](=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[CH3:8])[C:15]1=[O:16]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1ccc(C)cc1
Agent: Br
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1ccc(C)c2c1CC(C)C2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
6.66 g of p-xylene (62.10 mmol) were added at room temperature to a suspension of 10.51 g of AlCl3 (78.0 mmol) in 40 ml of chlorobenzene under nitrogen; the so obtained yellow suspension was cooled to 0° C. and 6.50 ml of 2-bromoisobutyrylbromide (52.6 mmol, AlCl3/p-xylene/2-bromoisobutyrylbromide=1.5/1.2/1.0) were added dropwise in about 2 min. The flask is connected to a water trap in which the produced HBr gas is neutralized with a base. At the end of the addition, the solution was allowed to reach ambient temperature. The so obtained red solution was stirred for 2 h. The reaction mixture was transferred into a flask containing 30 g of ice and 10 ml of 37% HCl, stirred for 15 min, then the organic layer was separated, and the aqueous layer washed with Et2O (2×100 ml). The combined organic layers were washed with a saturated solution of NaHCO3 in water, then with H2O. The solution was dried over Na2SO4 and then all volatiles were removed in vacuo to leave a slightly yellow oil (8.95 g, yield 98%).
Reaction SMILES: OO.B(F)(F)F.CC[O:9]CC.OC([C:16]1[C:17]([CH3:41])=[C:18]2[C:23]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[C:22]([C:38]#[N:39])[CH:21]=[N:20][N:19]2[CH:40]=1)(C)C>C(Cl)Cl>[OH:9][C:16]1[C:17]([CH3:41])=[C:18]2[C:23]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:29][CH:30]=3)=[C:22]([C:38]#[N:39])[CH:21]=[N:20][N:19]2[CH:40]=1
Reactant: CCOCC
Reactant: Cc1c(C(C)(C)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: FB(F)F
Agent: OO
Solvent: ClCCl
Product: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 83.5 %

Procedure:
34% H2O2 (53 μl, 0.058 mmol) was added to CH2Cl2 (3 ml) at −10° C., then BF3.Et2O (0.64 ml, 5.0 mmol) was added. After the mixture was stirred at −10° C. for 20 min, a suspension of 396 (165 mg, 0.42 mmol) in CH2Cl2 (2 ml) was added. The reaction was stirred at −10° C. for 5 min, then quenched with aq Na2SO3, extracted with EtOAc. The organic layer was dried, concentrated and purified by silica gel flash column chromatography to give 397A (125 mg, 85%) (10% EtOAc—CH2Cl2).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[CH:14][CH:13]=1
Reactant: COc1ccc(S)cc1
Reactant: OCc1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(Sc2ccccc2CO)cc1
Yield: 88.9 %

Procedure:
The general procedure in example 39 was followed. 2-Iodobenzylalcohol (234 mg, 1.0 mmol), 4-methoxythiophenol (123 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 2-(4-methoxyphenyl)sulfanylbenzylalcohol (219 mg, 89% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=5/1). Rf=0.3 (hexane/ethyl acetate=5/1). 1H NMR (CDCl3, 300 MHz) δ 7.40 (dd, 1 H, J=6.6 Hz, 1.5 Hz), 7.29 (dt, 2 H, J=8.7 Hz, 2.1 Hz), 7.13-7.21 (m, 2 H), 7.08 (dd, 1 H, J=8.1 Hz, 2.1 Hz), 6.86 (dt, 2 H, J=9.0 Hz, 2.1 Hz), 4.78 (d, 2 H, J=6.3 Hz), 3.80 (s, 3 H), 2.12 (t, 1 H, J=6.3 Hz). 13C NMR (CDCl3, 75 MHz) δ 159.7, 140.0, 135.9, 134.3, 130.8, 128.6, 128.5, 127.1, 124.5, 115.3, 63.9, 55.7. IR (neat, cm−1) 3365 (broad), 3015, 2962, 2904, 2867. MS (EI) m/z (relative intensity) 246 (100), 138 (40), 108 (70). HRMS (EI), Cald. for C14H14O2S 246.0709; Found 246.0707.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19]C(=O)C.O.OS(O)(=O)=O>CO.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]=1[NH2:19]
Reactant: CCCC(=O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCCC(=O)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 60 °C
Yield: 82.3 %

Procedure:
2-Acetylamino-5-butyryl-4-trifluoromethyl-benzoic acid methyl ester (234 mg, 0.706 mmol) was dissolved in MeOH (2.4 mL). Water (500 μL) was added, followed by dropwise addition of concd H2SO4 (254 μL). The reaction mixture was heated to 60° C. for 1 h to give a light yellow suspension. The reaction mixture was diluted with EtOAc, poured onto water/EtOAc and the pH was adjusted to 8 with sat. aq KHCO3. The organic phase was washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo. The obtained residue was purified by flash column chromatography (10 g silica gel, hexanes/EtOAc (1:0→7:3)) to afford the title compound (168 mg, 82%) as a colorless foam. ESI-MS: m/z 290 [M+H]+, m/z 288 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[OH:15].[Cl:16][CH2:17][C:18](Cl)=[O:19]>CC(C)CC(=O)C.O>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[OH:15])=[O:19]
Reactant: CCOC(=O)C(C)c1ccc(N)c(O)c1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)c1ccc(NC(=O)CCl)c(O)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of Ethyl 2-(4-amino-3-hydroxyphenyl)propanoate (101 mg, 0.483 mmol) in 4-methyl-2-pentanone (4 mL) was added chloroacetyl chloride (58 mg, 0.514 mmol) in 4-methyl-2-pentanone (2 mL) at room temperature. The reaction mixture was stirred for 12 hrs at 80° C. then cooled to room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[C:13]([OH:17])(=[O:16])[C:14]#[CH:15].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>[O-]S([O-])(=O)=O.[Cu+2].O.CC(O)(C)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]1[CH:15]=[C:14]([C:13]([OH:17])=[O:16])[N:7]=[N:6]1
Reactant: C#CC(=O)O
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-Difluorobenzyl azide (III) (7.0 g, 41.4 mmoles) is suspended in a H2O-tBuOH 1:1 mixture (120 ml), then propiolic acid (3.19 g, 45.6 mmoles), an ascorbic acid 1M solution (4.2 ml) and a CuSO4 0.3 M solution (1.4 ml) are added thereto. The reaction mixture is kept at 25° C. under stirring and is completed after 2 h. The mixture is left to cool at room temperature thereby precipitating the product. The solid is filtered off on a Buchner filter, washed with ethyl ether and dried under vacuum.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:38]=[CH:37][C:12]([NH:13][C:14]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH:24]=[CH:23][C:15]=2[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:14]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH:24]=[CH:23][C:15]=2[C:16]([OH:18])=[O:17])=[CH:37][CH:38]=1
Reactant: COc1ccccc1CCc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CCc1ccc(C(=O)O)c(Nc2ccc(F)cc2)c1
Yield: 12.6 %

Procedure:
Trifluoroacetic acid 7.5 mL solution of tert-butyl 2-(4-fluoroanilino)-4-(2-(2-methoxyphenyl)ethyl)benzoate 0.11 g was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-(2-(2-methoxyphenyl)ethyl)benzoic acid 12 mg of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH:10]=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[O:12]2)[CH:5]=1)([O-])=O.O.[NH2:22][NH2:23].[Cl-].[NH4+]>[Fe].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:12])[NH:23][N:22]=2)[CH:5]=1
Reactant: NN
Reactant: O=C1OC(=Cc2cc([N+](=O)[O-])ccn2)c2ccccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 90 °C
Yield: 31 %

Procedure:
A suspension of 3-(4-nitro-pyridin-2-ylmethylene)-3H-isobenzofuran-1-one (0.67 g, 2.5 mmol) in hydrazine monohydrate (0.25 g, 5.0 mmol) was heated to 90° C. for 1 hour and then cooled to room temperature. Ethanol (5 mL) added, followed by ammonium chloride (0.16 g, 3.0 mmol) and iron powder (0.28 g, 5.0 mmol), the mixture was then heated to 90° C. for 3 hours. The reaction mixture was filtered hot through celite which was washed with ethyl acetate (20 mL). The filtered was concentrated in vacuo and then diluted with ethyl acetate (10 mL) washed with brine (10 mL), dried over magnesium, sulphate and dried in vacuo to afford the title cpd as a pale yellow powder. Single peak in LC-MS analysis, (0.20 g, 31% yield) requiring no further purification, m/z (LC-MS, ESP), RT=1.58 (M+H) 253;
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH2:34](N)[CH2:35][NH2:36]>ClC1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]3[NH:36][CH2:35][CH2:34][N:21]=3)=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: NCCN
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C#N)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C2=NCCN2)CC1

Procedure:
To a solution of zinc chloride (28 mg, 0.149 mmol) and 4-[5-cyano-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (1 g, 2.09 mmol) in chlorobenzene (15 mL), ethane-1,2-diamine (0.100 mL, 1.463 mmol) was added. The mixture was heated under reflux for 24 h. LCMS indicated desired product. The crude was concentrated under vacuo and purified by HPLC to afford compound A92 as a yellow solid (303 mg, 23%). 1H NMR (CDCl3, 400 MHz) δ 1.23 (d, 6H), 1.68-1.77 (m, 2H), 2.05-2.09 (m, 2H), 3.07 (s, 3H), 3.16-3.23 (m, 2H), 3.84-3.92 (m, 2H), 4.07 (s, 4H), 4.87-4.92 (m, 1H), 5.42-5.47 (m, 1H), 7.50-7.62 (m, 2H), 7.79-7.83 (m, 1H), 8.35 (s, 1H). Exact mass calculated for C23H29FN6O5S 520.19, found 521.5 (MH+).
Reaction SMILES: C(C(NC(=O)OC(C)(C)C)(C)COCC1C=C(N(S(C)(=O)=O)CCC)N=C(Cl)C=1)C1C=CC=CC=1.CNCC1CC1C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(C(F)(F)F)=O.[NH2:66][C:67]([CH3:105])([CH2:98][C:99]1[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=1)[CH2:68][O:69][CH2:70][C:71]1[CH:76]=[C:75]([N:77]([CH2:83]C2C=CC=CC=2)[CH2:78][CH:79]2[CH2:81][CH:80]2[CH3:82])[N:74]=[C:73]([N:90]([CH2:95][CH2:96][CH3:97])[S:91]([CH3:94])(=[O:93])=[O:92])[CH:72]=1>ClC(Cl)C.CO.CCO>[NH2:66][C:67]([CH3:105])([CH2:98][C:99]1[CH:100]=[CH:101][CH:102]=[CH:103][CH:104]=1)[CH2:68][O:69][CH2:70][C:71]1[CH:76]=[C:75]([N:77]([CH3:83])[CH2:78][CH:79]2[CH2:81][CH:80]2[CH3:82])[N:74]=[C:73]([N:90]([CH2:95][CH2:96][CH3:97])[S:91]([CH3:94])(=[O:92])=[O:93])[CH:72]=1
Reactant: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(N(Cc2ccccc2)CC2CC2C)n1)S(C)(=O)=O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: CCO
Product: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(N(C)CC2CC2C)n1)S(C)(=O)=O

Procedure:
N-(4-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-propylmethanesulfonamide was prepared from intermediate VI and N-methyl-1-(2-methylcyclopropyl)methanamine (prepared from intermediate V) by methylation with formaldehyde in dichloroethane/methanol, in the presence of NaBH(OAc)3, followed by hydrogenation on Pd(OH)2, in EtOH, in the presence of TFA), following a similar procedure as described for the preparation of N-(4-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-6-{benzyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-propylmethanesulfonamide. HRMS (ES, M+H) calcd. for C26H40N4O3S: 489.2893, found: 489.2891.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1.C(Cl)(=O)C(Cl)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][C:41]=1[CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)[CH2:30][NH:31][C:32]1[C:33]([NH2:38])=[CH:34][CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1.NC1C=CC=CC=1>ClCCl.CN(C=O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][C:41]=1[CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)[CH2:30][NH:31][C:32]1[C:33]([NH:38][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])=[CH:18][CH:17]=2)=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1cc(CNc2ccccc2N)ccc1CN1CCCC1
Reactant: O=C(O)c1ccc(OCCN2CCCC2=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(CNc2ccccc2NC(=O)c2ccc(OCCN3CCCC3=O)cc2)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[2-(2-oxopyrrolidin-1-yl)ethoxy]-benzoic acid (250 mg, 1.0 mmol) in dry dichloromethane (10 mL) was added oxalyl chloride (0.184 mL, 2.1 mmol, 2.1 eq.) then a catalytic amount of DMF. After 1 h, the solvent was removed under reduced pressure. The residue was suspended in dry dichloromethane (9 mL) then added portionwise to a ) solution of N1-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]-1,2-benzenediamine (prepared according to Example 6, Part E) (292 mg, 0.94 mmol, 0.94 eq.) in dry dichloromethane (1 mL) and pyridine (0.182 mL, 2.25 mmol, 2.25 eq.) at 0° C. until all of the aniline had been consumed by tlc (9:1 CHCl3:MeOH). The reaction mixture was allowed to warm to ambient temperature then quenched with the addition of a saturated aqueous solution of sodium bicarbonate (10 mL). The reaction mixture was diluted with ethyl acetate (50 mL) then the layers were separated. The organic layer was dried (MgSO4), filtered, then concentrated under reduced pressure. The amide was obtained as a tan foam (140 mg, 26%) after flash chromatography (2-10% MeOH, 0.5% TEA in CHCl3).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:21])=[CH:15][CH:14]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH:37]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[NH:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH2:37][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[CH:15][CH:14]=1)[CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=Cc1nc2ccccc2[nH]1
Reactant: O=C(Nc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(Nc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Using general procedure B: Reaction of pyridine-2-carboxylic acid {4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-phenyl}-amide (AMD9409) (67 mg, 0.19 mmol), 1H-benzoimidazole-2-carbaldehyde (30 mg, 0.21 mmol), and NaBH(OAc)3 (119 mg, 0.50 mmol) for 0.5 h at 60° C. followed by purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 198:1:1) gave AMD9413 (48 mg, 53%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 1.62-1.75 (m, 1H), 1.96-2.07 (m, 2H), 2.23-2.30 (m, 1H), 2.68-2.91 (m, 2H), 3.74 (br s, 2H), 3.98 (d, 1H, J=16.8 Hz), 4.09 (m, 1H), 4.19 (d, 1H, J=16.5 Hz), 7.16-7.20 (m, 3H), 7.41-7.46 (m, 4H), 7.53 (d, 1H, J=6.0 Hz), 7.64-7.67 (m, 3H), 7.87 (ddd, 1H, J=7.5, 7.5, 1.5 Hz), 8.26 (d, 1H, J=7.8 Hz), 8.58 (d, 1H, J=3.9 Hz), 8.70 (d, 1H, J=3.3 Hz), 9.94 (br s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 21.39, 23.41, 29.22, 48.54, 53.54, 60.11, 119.57, 121.50, 122.25, 122.36, 126.37, 129.28, 134.71, 135.33, 136.73, 137.21, 137.62, 146.93, 147.93, 149.80, 157.47, 161.84. ES-MS m/z 489 (M+H). Anal. Calcd. for C30H28N6O.0.5H2O.0.3CHCl3: C, 68.23; H, 5.54; N, 15.76. Found: C, 68.06; H, 5.54; N, 15.46.