Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])[C:5]([O:7][CH3:8])=[O:6])=O.C1(C)C=CC(S([CH2:27][N+:28]#[C-])(=O)=O)=CC=1.C[O-].[Na+].O>CO>[CH3:8][O:7][C:5]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[CH:27][NH:28][CH:2]=1)=[O:6]
Reactant: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 58 %

Procedure:
With stirring, 20 g of methyl α-methylcarbonyl-2,3-dichlorocinnamate are added at 0° C. to a 22 % by weight solution of (p-tolylsulfonyl)methyl isocyanide prepared according to Example P1 (a). Then 26.3 g of a 30% solution of sodium methylate in methanol are added dropwise over 2 hours. The mixture is stirred for 2 hours and then 35 ml of water are added dropwise. The reaction mixture is concentrated at +50° C. under vacuum. After addition of 70 ml of water, the reaction mixture is concentrated once more under vacuum and then filtered. The filter residue is washed with toluene and recrystallised from ethanol, affording 10.8 g (58% of theory) of 4-methoxycarbonyl-3-(2,3-dichlorophenyl)-pyrrole which melts at 200°-201° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[N:25][C:26]=3[NH2:28])[N:21]([CH:29]3[CH2:34][CH2:33][N:32]([CH2:35][C:36]4[NH:37][CH:38]=[CH:39][N:40]=4)[CH2:31][CH2:30]3)[N:20]=2)=[CH:15][C:14]=1[O:41][CH3:42]>N1C=CC=CC=1>[NH2:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[N:21]([CH:29]3[CH2:34][CH2:33][N:32]([CH2:35][C:36]4[NH:37][CH:38]=[CH:39][N:40]=4)[CH2:31][CH2:30]3)[N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:9](=[O:10])[CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:14]([O:41][CH3:42])[CH:15]=3)[C:27]=12
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cc(-c2nn(C3CCN(Cc4ncc[nH]4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(Cc4ncc[nH]4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Reaction time: 2 h
Yield: 50.7 %

Procedure:
3-Phenylpropanoyl chloride (0.011 mL, 0.0715 mmol) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.0715 mmol) in pyridine (1.2 mL) at 0° C. After 2 hours, the solvent was evaporated and the residue was purified by flash column chromatography to give N1-(4-{4-amino-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide (20 mg, 51%). 1H NMR (CDCl3) δ 2.27 (m, 2H), 2.61 (m, 2H), 2.76 (m, 4H), 3.09 (m, 2H), 3.93 (s, 3H), 4.07 (s, 2H), 4.96 (m, 1H), 5.61 (bs, 2H), 7.06-7.33 (m, 10H), 7.78 (s, 1H), 8.35 (s, 1H), 8.55 (d, J=8.15 Hz, 1H). LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+ =552.5, Rt=1.83 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>C(Cl)Cl>[OH:10][CH2:9][C:4]1[CH:3]=[C:2]([NH:1][C:12](=[O:11])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(N)cc(CO)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1cc(CO)cc(NC(=O)OC(C)(C)C)c1

Procedure:
To a solution of (3-amino-5-methylphenyl)methanol (1.0 g, 7.29 mmol) in CH2Cl2 (30 mL) was added BOC2O (1.75 g, 8.02 mmol) at room temperature. After 24 hours the mixture was concentrated. Flash column chromatography (30% EtOAc/hexanes) gave tert-butyl 3-(hydroxymethyl)-5-methylphenylcarbamate as a white solid. 1H-NMR (300 MHz, CDCl3) δ 7.20 (s, 1H), 7.18 (s, 1H), 6.85 (s, 1H), 6.45 (bs, 1H), 4.60 (s, 2H), 3.60 (bs, 2H), 2.32 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([C:10]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=2)[C:13]2[CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][CH2:16][CH2:17][C:12]=2[N:11]=1)[CH2:8][CH3:9].[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>>[CH2:7]([C:10]1[N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:29][CH:30]=2)[C:13]2[CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:15]([C:44](=[O:47])[CH2:45][CH3:46])[CH2:16][CH2:17][C:12]=2[N:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)NCC2
Reactant: CCC(=O)Cl
Agent: O=C(O)C(=O)O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(C(=O)CC)CC2
Yield: 87 %

Procedure:
The compound obtained in Example 62 (1.0 g) is treated in the same manner as in Example 64 with using propionyl chloride (0.23 g) instead of acetic anhydride to give ethyl 2-n-propyl-5-propionyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.82 g) as a white foam.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]2[O:37][CH2:38][C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=2)=[CH:20][CH:19]=1)=O)C.C(O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O>[OH:13][CH2:14][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:26][CH:25]2[O:37][CH2:38][C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)C=Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C=CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
5 ml (5 mmol) of a solution of diisobutylaluminium hydride (DIBAH) (1M in hexane) were added dropwise at -50° C. to a solution of 698 mg (1.35 mmol) of tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 15 ml of toluene and the mixture was stirred at -50° C. for 30 minutes. Subsequently, the reaction mixture was treated dropwise at -50° C. with 10 ml of ethanol and warmed to room temperature. For the working-up, the reaction mixture was treated with 20 ml of water and 20 ml of saturated potassium sodium tartrate solution while cooling with ice and thereafter extracted three times with 50 ml of ethyl acetate each time. The organic phases were combined, dried over sodium sulphate and evaporated under reduced pressure. The crude product was chromatographed on silica gel using a 6:4 mixture of hexane and ethyl acetate as the eluent. There were obtained 354 mg (55% of theory) of tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propenyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 474 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]2[O:28][C:29]([CH2:32]Cl)=[N:30][N:31]=2)[CH:26]=1>>[Br:20][C:21]1[CH:26]=[C:25]([C:27]2[O:28][C:29]([CH2:32][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:3][CH:2]([CH3:19])[CH3:1])=[N:30][N:31]=2)[CH:24]=[N:23][CH:22]=1
Reactant: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Product: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 4 using 2-(2-methylpropyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J=1.4 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.43 (m, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 6.67 (s, 1H), 5.63 (s, 2H), 2.82 (d, J=7.1 Hz, 2H), 2.13 (m, 1H), 1.08 (d, J=6.6 Hz, 6H); MS (ES) m/z 504 (M+1, isotope for Br) and 506 (M+1, isotope for Br).
Reaction SMILES: [C:1](OC=C)(=[O:5])[CH2:2][CH2:3][CH3:4].[F:9][C:10]([F:18])([F:17])[C:11]([OH:16])([CH2:14][OH:15])[CH2:12][OH:13]>COC(C)(C)C>[C:1]([O:13][CH2:12][C@@:11]([OH:16])([CH2:14][OH:15])[C:10]([F:18])([F:17])[F:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: C=COC(=O)CCC
Reactant: OCC(O)(CO)C(F)(F)F
Solvent: COC(C)(C)C
Product: CCCC(=O)OC[C@@](O)(CO)C(F)(F)F
Temperature: 25 °C

Procedure:
Vinyl butyrate (1 ml) was added to a stirred mixture of 4 Å molecular sieves (2 g), lipase Amano PS precipitate (100 mg) and 2-(trifluoromethyl)-1,2,3-propanetriol (1 g) suspended in 1,1-dimethylethyl methyl ether (10 ml) and the mixture stirred at room temperature. The mixture was filtered through celite after 21.5 hours, washing with dichloromethane, concentrated, diluted with toluene (20 ml) and washed with saturated aqueous sodium chloride (2×20 ml), dried (Na2SO4) and evaporated to give a light yellow oil. 19F NMR spectroscopy displayed a 20:1 mixture of monoester/diester with no starting triol. The yellow oil was purified by chromatography over silica using a 1:1 mixture of dichloromethane/cyclohexane as eluent to remove the side products followed by elution with dichloromethane/ethyl acetate to afford the title compound as a pale yellow oil (0.64 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]=O)=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=3)[N:7]=[C:6]([C:25]#[N:26])[C:5]=2[N:4]=[N:3]1.[C@H:27]12[CH2:33][C@H:30]([NH:31][CH2:32]1)[CH2:29][N:28]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO.C(OCC)(=O)C>[C:25]([C:6]1[C:5]2[N:4]=[N:3][N:2]([CH3:1])[C:10]=2[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][N:31]3[CH2:32][C@@H:27]4[CH2:33][C@H:30]3[CH2:29][N:28]4[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[N:7]=1)#[N:26]
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(CCC=O)c(C(F)(F)F)c3)cc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(CCCN4C[C@@H]5C[C@H]4CN5C(=O)OC(C)(C)C)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
Methyl-6-(4-(3-oxopropyl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (200 mg), (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (221 mg) was dissolved in a mixed solvent of DCM (3 ml) and methanol (5 ml) containing acetic acid (0.4 ml). Sodium triacetoxyborohydride (350 mg) was then added in portions and the mixture was stirred at rt for further 3 hours. After diluting with ethyl acetate (100 ml), washed with sodium carbonate (30 ml), brine (20 ml), dried over sodium sulphate, solvent removed under vacuum, residue was then columned on silica gel using DCM:MeOH (20:1) as eluant to give (1S,4S)-tert-butyl 5-(3-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoro-methyl)phenyl)propyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (220 mg). 1H NMR (CDCl3) δ: 8.33 (s, 1H), 8.26 (d, 1H), 8.04 (s, 1H), 7.55 (d, 1H), 4.46 (s, 3H), 4.40 (br, 0.4H), 4.25 (br, 0.6H), 3.4-3.6 (m, 2H), 3.18 (m, 1H), 2.8-3.0 (m, 3H), 2.5-2.75 (m, 3H), 1.5-1.9 (m, 4H), 1.46 (s, 9H). MS m/z 542 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]2[N:12]([C:13]([CH:18]3[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[N:14][N:15]=2)[C:11]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([Mg]Cl)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]2[N:12]([C:13]([CH:18]3[CH2:19][CH2:20][C:21]([OH:24])([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:22][CH2:23]3)=[N:14][N:15]=2)[C:11]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCC(=O)CC2)C1
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCC(O)(c3ccccc3)CC2)C1
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 8-chloro-1-(4-oxo-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester (0.19 g, 0.46 mmol) in dry tetrahydrofuran (5 ml) was added a 2M phenyl magnesium chloride solution in tetrahydrofuran (0.24 ml, 0.48 mmol) at room temperature. After stirring for 2 h the reaction mixture was quenched with aqueous saturated ammonium chloride solution and extracted with three portions of tert-butyl methyl ether. The combined organic layers were washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.094 g, 42%) as white solid. MS m/e: 495 ([[M+H]]+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5]([NH:7][CH3:8])=O)[CH3:2].C(Cl)(Cl)=O.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH2:22][C:23]([NH:25][NH2:26])=O.Cl>ClC(Cl)Cl.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:7]([CH3:8])[C:23]([CH2:22][C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])=[N:25][N:26]=1)=[O:9])[CH3:2]
Reactant: NNC(=O)Cc1c(F)cccc1F
Reactant: CCOC(=O)C(=O)NC
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnc(Cc2c(F)cccc2F)n1C
Reaction time: 2 h

Procedure:
18.6 g (142 mmol) of oxalic acid monomethylamide monoethyl ester are dissolved under a nitrogen atmosphere in 63 ml of trichloromethane, and 59 ml of a 20% solution of phosgene in toluene are added thereto. At a temperature of 5-10°, 9.2 ml of pyridine are added dropwise. The reaction mixture is then stirred for 2 hours at 0°, nitrogen being blown through the reaction mixture during the second hour. 17.6 g (95 mmol) of 2,6-difluorophenylacetic acid hydrazide are then added The reaction mixture is subsequently stirred for 40 minutes at room temperature, then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted three times with ether. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution and extracted by shaking three times with dichloromethane. The combined dichloromethane phases are washed twice with water, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 160 ml of xylene and stirred under reflux for 9 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and the crystalline residue is recrystallised from ethyl acetate/ether. 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 127-128° is obtained.
Reaction SMILES: C1(C([NH:20][C@H:21]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.[H][H]>[Pd].CCO>[NH2:20][C@H:21]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC[C@H](N)C1
Yield: 100 %

Procedure:
To 13.7 g (30 mmol) of 1,1-dimethylethyl (3S)-3-[(triphenylmethyl)amino]azepane-1-carboxylate was carefully added 100 mL MeOH, 75 mL EtOH, and 1.00 g of 10% Palladium on charcoal. The mixture was hydrogenated on a Parr shaker under 30 psi of hydrogen gas for 15 h. The mixture was filtered through a pad of celite, and the filtrate concentrated to afford a quantitative yield (6.43 g) of product. The product was used as such without further purification.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][N:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CO>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:26]3[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCCl
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (130 mg, 0.398 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 6-formylnicotinate (86 mg, 0.518 mmol) and sodium triacetoxyborohydride (127 mg, 0.598 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated to give a crude product. The product was dissolved in methanol (2.000 mL) and sodium hydroxide (3M, 0.664 mL, 1.992 mmol) was added. The mixture was stirred at room temperature for 3 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions to give 110 mg of product as pale yellow solid (HCl salt). MS: (M+H)+=366.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (m, 1H),1.54-1.73 (m, 3H), 1.98-2.12 (m, 3H), 2.59-2.72 (m, 1H), 2.94 (m, 4H), 3.45 (br. s., 2H), 4.54 (br. s., 2H), 7.16-7.25 (m, 3H), 7.27-7.35 (m, 2H), 7.81 (d, J=8.08 Hz, 1H), 8.38 (dd, J=8.08, 2.27 Hz, 1H), 9.12 (d, J=1.52 Hz, 1H), 9.78 (br. s., 2H), 10.72 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[F:20])=[C:4]([CH3:21])[N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:24])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[F:20])=[C:4]([CH3:21])[N:3]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2O)c(F)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(F)c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
The product from step (ii) (6.6 g) was added to phosphorous oxychloride (40 ml) under nitrogen. The resulting mixture was stirred at 90° C. for 15 h. The phosphorous oxychloride was evaporated under reduced pressure and the residue cautiously diluted with water (50 mL). The aqueous phase was neutralised with NaHCO3 and heated at 50° C. for 1 h. The mixture was allowed to cool and the precipitate was collected by filtration. The solid was suspended in MeCN (40 mL) and collected by filtration to give the subtitle compound as a cream solid 3.70 g that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:32]1[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:32]4[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=4)=[CH:16][CH:15]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(Cl)c4)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 31.3 %

Procedure:
4-{5-[(3-chlorophenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (143.8 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 40 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 nm, of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a light-yellow solid (62.0 mg). Yield 31.3%.
Reaction SMILES: ClC1C=CC2N=C(C)C=CC=2C=1C(O)=O.[Cl:16][C:17]1[C:18]([NH:36][C:37](=[O:45])[CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([NH:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH:21]=[CH:20]2.FC(F)(F)C(O)=O>>[Cl:16][C:17]1[C:18]([NH:36][C:37](=[O:45])[CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([NH:27][CH2:28][C:29]([OH:31])=[O:30])[CH:21]=[CH:20]2
Reactant: CC(C)(C)OC(=O)CNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Agent: Cc1ccc2c(C(=O)O)c(Cl)ccc2n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Yield: 49.3 %

Procedure:
Prepared according to the method of example 7 (b), using N-[6-chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-glycine, 1,1-dimethylethyl ester (Example 40(a)) (63 mg) and trifluoroacetic acid (2 mL). Purification by HPLC (Symmetry—0.1% aqueous ammonium acetate/acetonitrile) afforded the title product (27 mg).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][NH:8][C:9]2[C:14]([I:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=O)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[CH:1]1([NH:4][C:5]2[N:10]3[CH:11]=[CH:12][CH:13]=[C:14]([I:15])[C:9]3=[N:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: O=C(NNc1ncccc1I)NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Ic1cccn2c(NC3CC3)nnc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A mixture of N-cyclopropyl-2-(3-iodopyridin-2-yl)hydrazinecarboxamide (preparation 26c, 0.56 g, 1.8 mmol) and phosphorous oxychloride (7 mL) was stirred at 75° C. overnight. The reaction mixture was cooled to ambient temperature, added slowly to an ice-water mixture and then was basified to pH 8 with aqueous sodium hydroxide solution. The aqueous solution was extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and the solvent evaporated in vacuo to yield the title compound (0.50 g, 88%) as a solid.