Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:26])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([CH3:25])=[CH:8]2)=[O:4].[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:26])[C:5]([C:3]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([CH3:25])[C:10]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1nc(C#N)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1cc2c(O)c(C(=O)NCC(=O)O)nc(C#N)c2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-3-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.29 mmol), glycine (2.86 g, 38 mmol) and NaOMe solution (57 mL, 29 mmol, 0.5M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 77 mg of the title compound as a white solid. MS: (+) m/z 382.08 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[OH:24][CH2:23][CH2:25][NH:26][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH2:12][C:11]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][O:9][CH:10]=2)=[N:15][CH:16]=1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Reactant: NCCO
Product: O=C(NCCO)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 72 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted using ethanolamine instead of 4-aminotetrahydropyran to the title compound (82 mg, 72%) which was obtained as a white solid. MS: m/e=341.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1)N(C)C
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1)N(C)C
Yield: 60.5 %

Procedure:
Following general procedure F, (6-bromo-4-{4-[1-(dimethylamino)ethyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (39 mg, 0.090 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (30 mg, 0.108 mmol) to afford the desired product (27 mg, 60%) as a light brown solid: 1H NMR (500 MHz, CD3OD) δ 8.81 (s, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.08-7.99 (m, 2H), 7.57-7.51 (m, 1H), 7.46 (dd, J=11.6, 2.2 Hz, 1H), 3.55 (d, J=11.5 Hz, 2-H), 3.27-3.13 (m, 3H), 2.78 (s, 5H), 2.63-2.51 (m, 1H), 2.02 (s, 1H), 1.95 (d, J=12.8 Hz, 2H), 1.82-1.67 (m, 2H), 1.41-1.19 (m, 8H), 0.90 (s, 1H); ESI MS m/z 496 [C28H31ClFN3O2+H]+; HPLC 98.4% (AUC), tR=10.58 min.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:6][N:5]=1)[CH3:2].C(OCC)(=O)C>CCOCC>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:6][N:5]=[C:4]2[S:3][CH2:1][CH3:2])=[CH:11][CH:12]=1
Reactant: CCSc1nnc(-c2ccccc2)n1Cc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCSc1nnc(-c2ccccc2)n1Cc1ccc(N)cc1
Yield: 82 %

Procedure:
Following the procedure of Example, 1, Part E, 3-ethylthio-4-(4-nitrobenzyl)-5-phenyl-4H-1,2,4triazole was reduced with stannous chloride to give (after multiple extractions with ethyl acetate in addition to ether) an 82% yield of the amine as a solid, mp 126.5°-127° C., homogeneous by TLC in 9:1 CH2Cl2 --MeOH, mass spectrum (FAB) m/e 311 (M+1)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl.[CH2:36]([O:38][C:39](=[O:42])[CH2:40][NH2:41])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])[N:14]=[C:13]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:41][CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:42])=[O:29])=[CH:31][CH:32]=3)[N:12]=2)=[CH:33][CH:34]=1)[CH:2]=[CH2:3]
Reactant: CCOC(=O)CN
Reactant: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(=O)OCC)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (100 mg, 0.21 mmol) in DCM (3 mL) was added glycine ethyl ester HCl (44 mg, 0.32 mmol), HATU (120 mg, 0.32 mol) and iPr2NEt (0.11 mL, 0.63 mmol). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. All solvents were removed under vacuum and the residue was purified by silica gel column (EtOAC/Hexanes=40% to 60%) to give ethyl 2-(4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetate (100 mg, 81%) as a white solid.
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[S:15][C:16]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=3)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=O)C.[OH-].[K+].CO>O>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[S:15][C:14]([C:11]3[CH:12]=[C:13]4[C:8]([CH2:7][CH2:6][CH2:5][NH:4]4)=[CH:9][CH:10]=3)=[N:18][C:17]=2[C:19]([OH:21])=[O:20])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCC3)sc1-c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2sc(-c3ccc4c(c3)NCCC4)nc2C(=O)O)cc1
Temperature: 55 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
To ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-(4-methoxyphenyl)thiazole-4-carboxylate (1K) (0.483 g, 1.11 mmol) and KOH (1.24 g, 22.1 mmol) was added MeOH (10 mL) and water (45 mL). The reaction mixture was allowed to heat to 55° C. and stirred 48 hours. The reaction was monitored by LCMS. To the reaction mixture was added (0.5 g, 8.9 mmol). The reaction mixture was allowed to heat to 55° C. and stirred for 24 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude residue was added EtOAc and water. The layers were separated and the aqueous extract was acidified to ˜pH6 with 1N HCl and extracted with EtOAc. The combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide 0.350 g (86%) of the desired product 5-(4-methoxyphenyl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylic acid (1L): LC/MS (APCI): m/z 367.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:20])[N:7]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[Br:21])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(-c2cccnc2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Br
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a solution of methyl-(2-pyridin-3-yl-thiazol-5-yl)-carbamic acid tert-butyl ester (100 mg, 0.34 mmol) in acetonitrile (2 mL) was added N-bromosuccinimide (122 mg, 0.68 mmol) in one portion and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a white solid (81 mg, 64%): mp 88-91° C.; IR (KBr) 1715 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.11 (s, 1H), 8.70 (d, J=4.2 Hz, 1H), 8.28-8.17 (m, 1H), 7.42 (dd, J=8.1, 4.8 Hz, 1H), 3.27 (s, 3H), 1.48 (s, 9H); ESIMS m/z 372 (M+2).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.Cl.[C:15]1([CH:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:29]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[CH:6]3)[CH2:25][CH2:24]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCCCn1cnc2ccccc21
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: c1ccc(C(OC2CCN(CCCn3cnc4ccccc43)CC2)c2ccccc2)cc1

Procedure:
A mixture of 6 parts of 1-(3-chloropropyl)-1H-benzimidazole, 7.6 parts of 4-(diphenylmethoxy)piperidine hydrochloride, 10.6 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethoxy)-1-piperidinyl]propyl}-1H-benzimidazole; mp. 110.2° C.
Reaction SMILES: [CH:1]([N:4]([CH:10]([CH3:12])[CH3:11])[C:5](=[O:9])[O:6][CH2:7]Cl)([CH3:3])[CH3:2].[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O-:35])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]/[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15].[Na+]>>[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O:35][CH2:7][O:6][C:5]([N:4]([CH:10]([CH3:12])[CH3:11])[CH:1]([CH3:3])[CH3:2])=[O:9])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]/[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C/c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)N(C(=O)OCCl)C(C)C
Agent: [Na+]
Product: CC(C)N(C(=O)OCOC(=O)C1=C(S/C=C/c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)C
Yield: 77.6 %

Procedure:
In the same manner as in Example 144, 90.9 mg of the title compound was prepared from 50.4 mg of chloromethyl N,N-diisopropylcarbamate and 87.8 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(E)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.O.[NH2:11][NH2:12]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH:11][NH2:12])=[N:6][CH:7]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncc(Br)cc1F
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution of 5-bromo-2,3-difluoropyridine (15 g, 77 mmol)) in EtOH (250 ml) was added hydrazine hydrate (19.36 g, 387 mmol), the mixture was heated to reflux and stirred overnight (16 hr). The solvent of the reaction mixture was evaporated about half under reduced pressure, then cooling in an ice bath there precipitation was occurred, filtered and washed the product with a minimum of EtOH and water, dried in vacuum to obtain pure desired product as white powder (15 g, yield 94%). LCMS (method A): [M+H]+=206.0, 208.0, tR=1.01 min.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[OH-].[K+]>CCOCC>[C:10]1([O:20][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Oc1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(C)NCC(O)COc1cccc2ccccc12
Temperature: 160 °C

Procedure:
To a mixture of 6.5 parts of 1-(tert.-butyl)-3-azetidinol and 7.9 parts of α-naphthol 0.2 part of potassium hydroxide was added, and the mixture was heated at 160° C. for 24 hours. The reaction mixture was cooled and then dissolved in 100 parts of ether. The solution was washed twice with 50 parts of 2 N-sodium hydroxide aqueous solution and extracted three times with 50 parts of 2 N-hydrochloric acid aqueous solution. The extract was washed with 50 parts of ether and made alkaline by addition of 2 N-sodium hydroxide aqueous solution. Extraction was conducted three times with 50 parts of benzene, and the extract was dried over anhydrous sodium sulfate. Then benzene was distilled off and the residue was solidified by drying under reduced pressure. The solid residue was subjected to distillation under reduced pressure. As a result, 5 parts of 1-(α-naphthoxy)-3-(tert.-butylamino)-2-propanol boiling at 175°-180° C. under 1.5 mm Hg were obtained. A part of the product was dissolved in 5 parts of anhydrous ether and the product was converted to a hydrochloride by adding a hydrochloric acid gas to the resulting ether solution. The hydrochloride was recrystallized twice from a mixed solvent of ethyl acetate and ether. As a result, 1-(α-naphthoxy)-3-(tert.-butylamino)-2-propanol hydrochloride having a melting point of 182°-184° C. was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][NH:24]3)[N:13]=2)=[CH:8][CH:7]=1.[C:31]([CH2:33][C:34](O)=[O:35])#[N:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:34](=[O:35])[CH2:33][C:31]#[N:32])[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][C:4]4[CH:28]=[CH:29][CH:30]=[C:2]([F:1])[CH:3]=4)=[CH:7][CH:8]=3)[C:20]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3)cc1)nn2C[C@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
Into a 100-mL round-bottom flask, was placed 3-[4-(3-fluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (216 mg, 0.53 mmol, 1.00 equiv), 2-cyanoacetic acid (36.8 mg, 0.43 mmol, 0.80 equiv), HATU (166 mg, 0.44 mmol, 0.80 equiv), triethylamine (109 mg, 1.08 mmol, 2.00 equiv), N,N-dimethylformamide (50 mL). The resulting solution was stirred for 3 h at 25° C. The resulting solution was extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane methanol (50 1) to give 150 mg (60%) of 3-[(2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Solvent: CCO
Product: Nc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.9 %

Procedure:
In ethanol (300 ml) was dissolved 4-(4-nitrobenzyl)morpholine (25.8 g), and to the mixture was added dried 10% palladium on carbon (Pd—C) (1.00 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was separated and purified with column chromatography (ethyl acetate) to give 4-(4-aminobenzyl)morpholine (430 mg) as pale yellow crystals.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:24])[CH:16]=1.C=O>C1COCC1.O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:22][CH:23]=1)[C:19](=[O:21])[O:20][CH2:1][CH2:24]2
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCOC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (33.5 ml) in dry THF (190 ml) was added dropwise, at −78° C., n-butyllithium (1.6 M solution in hexane, 145.9 ml). Subsequently, the reaction mixture was warmed to room temperature for 5 minutes and then cooled again to −78° C., and a solution of 4-methoxy-2-methylbenzoic acid (10 g) in dry THF (210 ml) was added dropwise. After stirring at this temperature for 10 minutes, paraformaldehyde (7 g) was added. The reaction mixture was then allowed to come to room temperature and stirred at this temperature for 4 hours. The reaction mixture was admixed with water, then the THF was removed under reduced pressure and then the aqueous phase was extracted with diethyl ether. The aqueous phase was acidified with conc. HCl, and the resulting precipitate was filtered off and washed repeatedly with water. The product was thus obtained with the molecular weight of 178.06 (C10H10O3); MS (ESI): 179 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH:13]([C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Nc1ccccc1
Solvent: CCO
Product: CC#CCOc1cc(Nc2ccccc2)ncn1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
In 1.1 ml of ethanol were dissolved 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 0.15 g of aniline, followed by heating under reflux for 7 hours. The reaction mxiture was then left for cooling to room temperature and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.13 g of 4-anilino-6-(2-butynyloxy)pyrimidine (the present compound (53)), m.p.: 159.3° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[C@:17]([CH3:21])([CH2:19][CH3:20])[NH2:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:23][CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:19]([C@@:17]1([CH3:21])[NH:18][C:26](=[O:28])[N:15]([C:12]2[CH:13]=[N:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:10][CH:11]=2)[C:16]1=[O:22])[CH3:20]
Reactant: CC[C@](C)(N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3ccc(C)c(OC)c3)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
To a solution of N1-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-isovalinamide (Reference Intermediate R8 42 mg) in dry dichloromethane (6 mL), TEA (0.089 mL, 0.638 mmol) was added. The mixture was cooled down to 0° C. and a solution of triphosgene (17.03 mg, 0.057 mmol) in dry dichloromethane (1.500 mL) was added dropwise. The mixture was stirred at that temperature for 1 hour, then a solution of triphosgene (17.03 mg, 0.057 mmol) in dry dichloromethane (DCM) (1.500 mL) was added dropwise again. The reaction was stirred for 30 minutes, it was maintained in the ice-bath and quenched with water (10 mL). The mixture was allowed to reach the room temperature then it was extracted with dichloromethane (3×7 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue obtained was purified by flash chromatography on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate as eluents from 80/20 to 50/50 (Biotage system). This afforded the title compound as a white solid (24 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:29](=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)=[O:40])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(C2CN(Cc3ccccc3)CCO2)cc1)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 34.6 %

Procedure:
To a solution of 4-benzyl-2-(4-bromo-phenyl)-morpholine (1.89 g, 5.7 mmol) in THF (30 mL), at −78° C., was added dropwise n-butyl lithium (2.85 mL; 2.5 mol/l in hexanes; 7.1 mmol). The mixture was stirred for 20 min. at −78° C., and subsequently N-Methoxy-N-methyl-3-trifluoromethyl-benzamide (2.66 g, 11.4 mmol) was added. The mixture was allowed to warm to RT and stirred overnight. The resulting mixture was partitioned between an aqueous saturated NH4Cl solution and EtOAc. The layers were separated. The organic layer was washed with a saturated aqueous NaHCO3-solution, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:heptanes 1:3) to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-methanone (0.84 g), which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][NH:20][CH:21]1[CH2:23][CH2:22]1.C(N(CC)CC)C>O1CCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][N:20]([CH:21]1[CH2:22][CH2:23]1)[C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[F:1])=[O:10]
Reactant: Clc1cc(-c2ccccc2)ccc1CNC1CC1
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(F)c1C(=O)N(Cc1ccc(-c2ccccc2)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
At ambient temperature, a solution of 226 mg (1.28 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 300 mg (1.164 mmol) of N-[(3-chlorobiphenyl-4-yl)methyl]cyclopropanamine and 0.18 ml of triethylamine in 5 ml tetrahydrofurane. The reaction mixture is stirred for 15 hrs at room temperature. The solvent is removed under vacuum and 10 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×50 ml) and the combined organic layers are successively washed by a 1M solution of HCl, a saturated solution of potassium carbonate and brine and filtered over a ChemElut cartridge to yield after concentration 350 mg (72% yield) of N-[(3-chlorobiphenyl-4-yl)methyl]-N-cyclopropyl-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide as a yellow oil (M+H=398).