Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:15]([S:19](Cl)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]>C1COCC1.C(Cl)Cl>[CH2:15]([S:19]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)Nc1ccncc1
Temperature: 50 °C
Reaction time: 19 h
Yield: 25.8 %

Procedure:
51.0 g of 4-aminopyridine (0.542 mol) and 75.0 ml of triethylamine (54.8 g, 0.542 mol) were dissolved at 50° C. in 540 ml of THF. Again at 50° C., 70.3 ml of n-butanesulphonyl chloride (84.9 g, 0.542 mol) were added dropwise to this solution over the course of 1 h. After 19 h of stirring at 50° C. the reaction mixture was diluted with 500 ml of methylene chloride and extracted twice with 500 ml of 1 N NaOH. The aqueous phase was adjusted to a pH of 6-7 with concentrated HCl and then extracted with 500 ml of methylene chloride. The organic phase was dried over magnesium sulphate and the methylene chloride was removed by distillation. The 30 g of crude product obtained were recrystallized from acetonitrile. This gave 19.0 g of clean product. The constitution of the compound was verified by NMR-spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH:9]([CH2:20][OH:21])[CH2:10][CH2:11][N:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])([CH3:4])([CH3:3])[CH3:2].[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH:9]([CH2:20][O:21][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:10][CH2:11][N:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(CO)CCn1ccc(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(CCn1ccc(=O)[nH]c1=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 81.3 %

Procedure:
A glass tube for microwave was charged with compound 41 (50 mg; 0.155 mmol), trityl chloride (54 mg; 0.19 mmol) and dry pyridine (2 ml). The tube was sealed with a septum cap. The vial was irradiated with MW to reach the temperature of 160° C. for 5 minutes. The irradiating cycle was repeated 3 times, and then the mixture was poured into a round bottom flask. The solvent was removed under reduced pressure and the crude was purified by chromatography using Hexane/EtOAc 40:60 as eluent which gave the title product as a white foam (70 mg, 79%). Rf: 0.27 in Hexane/EtOAc 40:60, M.p: 86-88° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[Cl:12].[CH2:14]([CH:16]([NH2:19])[CH2:17][CH3:18])[CH3:15]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([NH:19][CH:16]([CH2:17][CH3:18])[CH2:14][CH3:15])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[Cl:12]
Reactant: CCC(N)CC
Reactant: COC(=O)c1c(Cl)cc(C)nc1Cl
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Cl)c1C(=O)OC
Temperature: 110 °C
Yield: 42.5 %

Procedure:
A mixture of 2,4-dichloro-6-methyl-nicotinic acid methyl ester (2.228 g, 10.13 mmol) and 1-ethyl-propyl amine (1.762 g, 20.26 mmol) in DMSO (4 ml) was heated at 110° C. for 5 hours, then at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentratd to give 1.796 g of crude material. The crude material was purified through silica gel column chromatography using chloroform to 5% methanol in chloroform as eluent to give 1.167 g (43%) of the title compound as a colorless oil. 1H NMR (CDCl3) 657.14 (brs, 1H), 6.27 (s, 1H), 3.86 (s, 3H), 3.27 (m, 1H), 2.33 (s, 3H), 1.3-1.6 (m, 4H), 0.88 (t, 6H) ppm.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and benzoyl chloride: Anal. Calcd for C31H37N3O2+0.55CHCl3: C, 69.0; H, 6.89; N, 7.65. Found: C, 69.7; H, 6.73; N, 6.03; ESMS m/e: 484.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[CH:10]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:22])=O.O.[OH-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[CH:10]=2)=[C:6]([Cl:22])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (1.0 g) in DMF was added phosphoric trichloride (1.07 ml) at −40° C. for 20 minutes. This reaction mixture was warmed to −10° C. and stirred for 1 hour. To this solution was added water (40 ml) and stirred at 40° C. for 14 hours. The pH of the resulting suspension was adjusted to 4.5 with 30% The pH of the aqueous mixture was adjusted to 6-7 with 12% aq. NaOH. The precipitate was collected by filtration and washed with water to give 3-amino-5-chloro-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (263 mg) as a yellow powder.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.[OH2:19]>C1COCC1.CC(O)(C)C>[Br:1][C:10]1([CH3:9])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19]
Reactant: Cc1c[nH]c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Reactant: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC1(Br)C(=O)Nc2ccccc21

Procedure:
N-Bromosuccinimide (NBS) (5.42 g, 30.49 mmol) was dissolved in cold THF (100 mL) The resulting THF solution was then added dropwise via addition funnel to a stirring solution of 3-methylindole LXXXIII (2.00 g, 15.25 mmol) in mixed t-BuOH (100 mL) and H2O (1 mL) at rt over a period of one hour. After stirred for an additional hour, the solution was concentrated under reduced pressure and the crude material was directly purified by silica gel column chromatography (EtOAc-hexanes 1:4) to give 3-bromo-3-methyl-2-indolinone as a pale yellow solid 3-bromo-3-methyl-2-indolinone LXXXIV (2.52 g, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:12]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:8]1[N:6]2[N:7]=[C:2]([CH3:1])[CH:3]=[C:4]([CH3:11])[C:5]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c2nccn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c2ncc(Br)n2n1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a solution of 3.63 g (24.7 mmol) of 6,8-dimethylimidazo[1,2-b]pyridazine in 25 mL of chloroform was added 4.84 g (27.2 mmol) of N-bromosuccinimide. After 2 h, 1 mL of a saturated aqueous solution of sodium bicarbonate was added. The layers were separated. The organic layer was dried (Na2SO4) and the solvent was removed with a rotary evaporator. The residue was purified by flash chromatography to give 4.66 g of the title compound as a white solid, m.p. 137°-139° C.
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=O)=[O:6].Cl.[NH2:24][OH:25].N1C=CC=CC=1>CN(C=O)C>[O:1]=[C:2]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=[N:24][OH:25])=[O:6]
Reactant: O=C[C@@H]1CCCN1C(=O)CCC(=O)NCc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(CCC(=O)N1CCC[C@H]1C=NO)NCc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of N-[4-oxo-4-(4-chlorobenzylamino)butanoyl]-L-prolinal (304 mg) in DMF (2.5 ml) were added hydroxylamine hydrochloride (75 mg) and pyridine (90 μl), and the mixture was stirred at 70° C. for 2 hours. To a solution of crude (2S)-1-[4-oxo-4-(4-chlorobenzylamino)butanoyl]-2-pyrrolidinecarboxaldehyde oxime as obtained by subjecting the reaction mixture to concentration under reduced pressure, in methylene chloride (4 ml) were added pyridine (0.16 ml) and acetic anhydride (0.19 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was treated in the same manner as in Example 15 to give 249 mg of (2S)-1-[4-oxo-4-(4-chlorobenzylamino)butanoyl]-2-pyrrolidinecarboxaldehyde O-acetyloxime.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:32])[C:15]1[C:20](Br)=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:16]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]>COCCOC.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:13][C:14](=[O:32])[C:15]1[C:20]([CH:8]=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:16]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]
Reactant: COC(=O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C=Cc2ccccc2)cc(F)c(F)c1Nc1ccccc1Cl
Temperature: 90 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
Pd(PPh3)4 (0.313 g, 0.271 mmol) and trans-2-phenylvinylboronic acid (1.105 g, 7.468 mmol) were added to a mixture of 6-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (2.00 g, 5.31 mmol) in 35 mL DME and 8 mL 2.0 M aqueous K2CO3 solution. The reaction mixture was heated under a N2 atmosphere to 90° C. and stirred for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water and the layers separated. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography gave 1.20 g (56%) clean desired product.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]\[CH2:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([C:28](=O)[CH3:29])[CH:25]=[CH:26][CH:27]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]\[CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:1])=[CH2:29])[CH:23]=1)[CH3:20]
Reactant: [Li]CCCC
Reactant: CC(=O)c1cccc(CN(C)C/C=C\C#CC(C)(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(C)C/C=C\C#CC(C)(C)C)c1
Yield: 14 %

Procedure:
The procedure described in Example 2 was repeated, except that methyl triphenylphosphonium bromide (7.65 g; 21.4 mmol), n-butyl lithium in n-hexane (1.63 M: 4.4 ml; 23.5 mmol), and Compound 4 (7.65 g; 21.4 mmol) were used, to thereby yield 0.65 g of the target compound (yield: 14.0%).
Reaction SMILES: [C:1]([NH:4][C:5](=S)[NH:6][C:7]1[N:12]=[C:11]2[N:13]([CH2:25][CH3:26])[C:14]([C:16]([N:18]([CH:22]3[CH2:24][CH2:23]3)[CH:19]3[CH2:21][CH2:20]3)=[O:17])=[CH:15][C:10]2=[C:9]2[N:27]([CH3:30])[CH:28]=[N:29][C:8]=12)(=O)[CH3:2].[CH3:32][NH:33][NH2:34]>C(O)(=O)C>[CH:19]1([N:18]([CH:22]2[CH2:23][CH2:24]2)[C:16]([C:14]2[N:13]([CH2:25][CH3:26])[C:11]3=[N:12][C:7]([NH:6][C:5]4[N:4]=[C:1]([CH3:2])[N:33]([CH3:32])[N:34]=4)=[C:8]4[N:29]=[CH:28][N:27]([CH3:30])[C:9]4=[C:10]3[CH:15]=2)=[O:17])[CH2:20][CH2:21]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)NC(C)=O)nc21
Reactant: CNN
Solvent: CC(=O)O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)n(C)n3)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 30.8 %

Procedure:
A mixture of 4-(3-acetylthioureido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 125A, 17 mg, 0.039 mmol) and methylhydrazine (2.486 μL, 0.046 mmol) in acetic acid (0.5 mL) was heated at 80° C. for 4 h, LC/MS showed starting material still remaining. Additional methylhydrazine (2.486 μL, 0.046 mmol) was added and heating continued for another 2 h, reaction complete. Solvent was evaporated and the crude was purified by preparative HPLC to furnish N,N-dicyclopropyl-4-(1,5-dimethyl-1H-1,2,4-triazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (5.2 mg, 30.7% yield) as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:18]([Br:30])(Br)[C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C1CCCCC1.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[O:16]=[C:8]1[N:37]2[C:38](=[CH:39][C:40](=[C:18]([Br:30])[C:19]3[CH:28]=[N:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH:41]=[CH:42]2)[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c(-c2ccccc2)c1-c1ccccc1
Reactant: c1ccncc1
Reactant: BrC(Br)(Br)c1cnc2ccccc2n1
Solvent: C1CCCCC1
Product: O=C1C(c2ccccc2)=C(c2ccccc2)C2=CC(=C(Br)c3cnc4ccccc4n3)C=CN12

Procedure:
A solution of one equivalent of 2,3-diphenyl cyclopropenone and two equivalents of 2-tribromomethylquinoxaline in pyridine were heated on a steam bath for five minutes, flooded with cyclohexane and filtered to furnish the crude dye. Chromatography on silica gel furnished a purified sample, λmax =500 nm. A minor product of the reaction obtainedfrom the chromatography was 1-oxo-2,3-diphenyl-7-[bromo(2-quinoxylinyl)methylidene]-7H-indolizine, λmax =600 nm.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cc[nH]c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccn(-c2ccc(F)cc2)c1
Yield: 35.7 %

Procedure:
To a dichloromethane solution (4.0 mL) of 3-nitropyrrole (200 mg, 1.78 mmol), 4-fluorophenylboronic acid (499 mg, 3.57 mmol), and copper acetate (II) (486 mg, 2.68 mmol), N,N-diisopropylethylamine (606 μL, 3.57 mmol) was added and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was filtered with Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (131 mg, yield 36%).
Reaction SMILES: N[C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([NH2:19])=[O:18].[CH2:20]=O.[C:22]([BH3-])#[N:23].[Na+].[OH-].[Na+]>C(#N)C.C(O)(=O)C>[C:8]([C:7]1[C:2]([N:23]([CH3:22])[CH3:20])=[C:3]([CH2:16][C:17]([NH2:19])=[O:18])[CH:4]=[CH:5][CH:6]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [BH3-]C#N
Reactant: NC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)c1c(CC(N)=O)cccc1C(=O)c1ccccc1

Procedure:
A solution of 12.7 g (0.05 mol) of 2-amino-3-benzoyl-phenylacetamide in 150 ml of acetonitrile is treated four times with 16 ml (0.2 mole) of 37% formalin, 6.4 g (0.1 mole) of sodium cyanoborohydride and 2 ml of glacial acetic acid with a 15 minute stirring period between each treatment. The mixture is finally poured into dilute sodium hydroxide and extracted three times with diethylether. The ether extracts are combined, dried over magnesium sulfate and concentrated. The product is isolated by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)[CH:19]=[N:20][C:15]4=[N:14][N:13]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[CH:30]1([NH:33][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([C:18]3[CH:19]=[N:20][C:15]4[N:16]([C:12]([C:9]5([C:6]6[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=6)[CH2:10][CH2:11]5)=[N:13][N:14]=4)[N:17]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31]1
Reactant: COc1ccc(C2(c3nnc4ncc(-c5ccc(C(=O)O)cc5)nn34)CC2)cc1
Reactant: NC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C2(c3nnc4ncc(-c5ccc(C(=O)NC6CC6)cc5)nn34)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoic acid (isomer-I from step 2, 14.0 mg, 0.0361 mmol), cyclopropylamine (3.76 μL, 0.0542 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.0 mg, 0.0361 mmol) and N,N-diisopropylethylamine (25.2 μL, 0.145 mmol) in DMF (1.0 mL) was stirred at RT for 3 h. The mixture was diluted with methanol and purified by RP-HPLC (pH=10) to give the desired product. Analytical LCMS: (M+H)+=427.3.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:23]=[CH:24][C:25]=1[F:26]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(F)c(Cl)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(F)c(Cl)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(3-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[CH2:36]O)[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.S(Cl)([Cl:41])=O>ClCCl.CN(C=O)C>[F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[CH2:36][Cl:41])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4CO)C3)cs2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4CCl)C3)cs2)CC1

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(hydroxymethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (0.55 g) in dichloromethane (10 ml) were added, at room temperature, thionyl chloride (0.24 g) and one drop of DMF, and the mixture was then refluxed for 2 hours. Subsequently, the reaction mixture was concentrated under reduced pressure. This gave, without further purification, 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(chloromethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (0.59 g).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4]([OH:6])=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)=[O:28])[CH3:25].CN1CCOCC1>ClCCl>[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:4](=[O:6])[CH:3]([CH2:1][CH3:2])[CH2:7][CH3:8])=[O:28])[CH3:25]
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: CCC(CC)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCN1C(=O)C(CC)CC
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To dichloromethane solution (350 ml) of 2-ethyl butanoic acid 5.68 g (48.9 mmol) under cooling on ice-water, HOBt 6.76 g (50 mmol), EDC 9.6 g (50 mmol) were added, stirring was continued for 30 min. 2(S)-pyrrolidine-carboxylic acid ethylester hydrochloride 8 g (45 mmol), NMM 4.55 g (45 mmol) were added to the reaction mixture and then stirred at room temperature for overnight. After then, the reaction mixture was washed with water, 1% sodium hydroxide solution, and then water sequentially. The organic layer was dried over sodium sulfate and the solvents were removed in vacuo. Purification by silica gel chromatography gave a desired product as an oil (8.16 g). NMR was consistent with the desired title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.CN(C1CCCCC1)C1CCCCC1.Cl[CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:7]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn[nH]c12
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-tert-butyl 4-((1-(5-bromo-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (340 mg, 0.639 mmol) and N-methyldicyclohexylamine (0.205 mL, 0.958 mmol) in tetrahydrofuran (2 mL) at 0° C. was added (2-(chloromethoxy)ethyl)trimethylsilane (0. 159 mL, 0.894 mmol). The ice bath was removed and the reaction stirred at room temperature overnight. The reaction was poured into diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% EtOAc/Hex) gave 383 mg (91%) as a foam. 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.66 (s, 1H), 7.30 (m, 2H), 7.02 (m, 2H), 6.89 (s, 1H), 5.64 (qAB, JAB=10.7, 2H), 4.92 (q, J=6.4, 1H), 3.71 (m, 2H), 3.59 (m, 2H), 3.35 (qAB, JAB=9.2, 2H), 3.05 (m, 2H), 2.18 (m, 1H), 2.06 (m, 1H), 1.93 (m, 1H), 1.86 (m, 1H), 1.42 (m, 12H), 0.90 (m, 2H), −0.07 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 162.4, 160.5, 155.1, 145.6, 138.8, 135.9, 128.9 (d, J=7.7), 124.9, 123.6, 122.2, 121.1, 116.2, 115.3, 115.2, 81.9, 79.4, 77.9, 73.9, 67.6, 41.3, 40.3 (br), 32.3, 31.9, 28.6, 22.9, 17.9, −1.3.