Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:11]([OH:15])(=[O:14])[CH:12]=[O:13]>CC(C)=O>[C:1]([NH:9][CH:12]([OH:13])[C:11]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(O)C(=O)O)c1ccccc1
Yield: 100 %

Procedure:
The titled compound 65 was prepared according to a procedure described by Zoller et al.209 A mixture of benzamide 35 (5.00 g, 41.3 mmol) and glyoxylic acid monohydrate 41 (4.32 g, 46.9 mmol) in anhydrous acetone (70 mL) was heated at reflux for 19 h. The reaction mixture was evaporated under reduced pressure to afford the desired product 65 as a colourless solid (8.06 g, 100%), m.p. 198-200° C. (lit.209 200-201° C. (dec)) Spectroscopic data indicated the crude product 65 did not require purification and was used directly in the subsequent reaction (Section 7.11.4). νmax (KBr): 3310bs, 3058w, 1728s, 1646s, 1602w, 1582w, 1535s, 1491w, 1452w, 1315m, 1292w, 1254m, 1161m, 1097s, 1040m, 1002w, 957m, 805w, 770w, 728m, 692m, 654m, 609w, 515m, 483w cm−1. 1H n.m.r. (300 MHz, D6-DMSO): δ 5.60 (d, J=7.8 Hz, 1H, H2), 7.41-7.49 (m, 2H, H3′, 5′), 7.55 (m, 1H, H4′), 7.86-7.92 (m, 2H, H2′, 6′), 9.26 (d, J=7.8 Hz, 1H, NH), two exchangeable OH protons not observed. 13C n.m.r. (75 MHz, D6-DMSO): δ 71.7 (C2), 127.6, 128.3, 131.7 (Arom CH), 133.7 (C1′), 166.0, 171.5 (C1, CONH). Mass Spectrum (ESI+, MeOH): m/z 218.2 (M+Na)+, C9H9NNaO4 requires 218.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[C:27]([Cu])#[N:28].CN1C(=O)CCC1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:27]#[N:28])[N:11]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)c(F)c1
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)c(F)c1

Procedure:
2,3-Dibromo-1-(3,4-difluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (4.98 g) was brominated similar to the synthesis of Example 103(a) to give the crude tribromo product, which was subjected to a cyanation condition CuCN/NMP similar to that of Example 105(a) to give the C-7 CN title product. The title compound, ESI MS (m/z): 514 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1.[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:19].[B-](F)(F)(F)F.CNC>CO>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:18]([CH3:19])[CH3:17])=[O:16])[CH2:12][CH2:13]1
Reactant: Nc1cnccc1N1CCC(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CO
Product: CN(C)C(=O)C1CCN(c2ccncc2N)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A microwave vial was charged with 1-(3-amino-4-pyridyl)piperidine-4-carboxylic acid (125 mg, 0.197 mmol), TBTU (200 mg, 0.62 mmol) and N-methylmethanamine (3.5 mL, 2M in MeOH). The tube was sealed and the mixture stirred for 3 h at 120° C. The crude was redissolved in MeOH and loaded into a MeOH pre-washed SCX column, rinsed with MeOH and the product was released with methanolic ammonia. The ammonia extracts were concentrated under reduced pressure to yield 1-(3-aminopyridin-4-yl)-N,N-dimethylpiperidine-4-carboxamide. MS (ES+) 249.2.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][C:8]=1[Cl:22])[CH3:6])=[O:4].[C:23]([O:27][C:28](=[O:45])[CH2:29][NH:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[C:23]([O:27][C:28](=[O:45])[CH2:29][N:30]([CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][C:8]=1[Cl:22])[CH3:6])=[O:4])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)CNCc1cccc(C(=O)OC(C)(C)C)c1
Reactant: CN(C(=O)CCl)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C(=O)CN(CC(=O)OC(C)(C)C)Cc1cccc(C(=O)OC(C)(C)C)c1)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 2-chloro-N-(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-N-methylacetamide (500 mg) in acetonitrile (8.95 mL) were added tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (441 mg), potassium carbonate (285 mg), and potassium iodide (22.8 mg), followed by stirring at 60° C. overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl){2-[(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)(methyl)amino]-2-oxoethyl}amino]methyl}benzoate (809 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=3[C:14](O)=[O:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.O.[NH2:24][NH2:25]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:12]4[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:14](=[O:15])[NH:25][N:24]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(C(=O)c2ccc3c(c2)OCO3)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(-c3ccc4c(c3)OCO4)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(1,3-benzodioxol-5-yl)carbonyl-5-methoxybenzoic acid unpurified with hydrazine hydrate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.[C:9]([C:12](=[CH:18]OCC)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:11])[CH3:10]>C(O)C.[Pd]>[C:9]([C:12](=[CH:18][NH:1][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:11])[CH3:10]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(=CNc1cn[nH]c1)C(C)=O
Reaction time: 3.5 h
Yield: 69 %

Procedure:
A solution of 4-nitropyrazole (5.6 g, 50 mmol)in ethanol (200 ml) was hydrogenated over 10% palladium on charcoal (0.5 g) at room temperature and pressure for 3.5 h. The catalyst was filtered off and ethyl 2-acetyl-3-ethoxyacrylate (9.3 g, 50 mmol) was added to the solution under nitrogen. After 5 min, the solution was evaporated in vacuo and the residual solid was recrystallised from ethyl acetate/pentane (charcoal) to give the title compound (7.7 g, 69%), m.p. 126°-128° C. Found: C, 49.96; H, 6.28; N, 17.34%. C10H13N3O3.H2O requires C, 49.78; H, 6.27; N, 17.41%.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([C:28]1[N:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][N:29]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.Cl[C:50]1[C:55]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:54][N:53]=[C:52]([C:61]([F:64])([F:63])[F:62])[N:51]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[F:46][C:43]([F:45])([F:44])[C:41]1[CH:40]=[C:5]([CH:4]=[C:3]([C:2]([F:48])([F:1])[F:47])[CH:42]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][C:10]=1[C:54]1[C:55]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:50][N:51]=[C:52]([C:61]([F:63])([F:64])[F:62])[N:53]=1)[C:28]1[N:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:32][N:33]=1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCOCC3)cn2)OC1(C)C
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amine (250 mg) is dissolved in 1,4-dioxane (5 ml) and thereto are added ethyl 4-chloro-2-trifluoromethyl-pyrimidine-5-carboxylate (140 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (30 mg) and cesium carbonate (177 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate and the insoluble materials are removed by filtration through Celite™. The filtrate is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-2-trifluoromethyl-pyrimidine-5-carboxylate (199 mg). MS (m/z): 783 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[CH:15]=[C:16]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28](C)[C:29](=O)OC(C)(C)C)[CH2:22][CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[N:12]=[C:11]([C:37]([F:40])([F:39])[F:38])[CH:10]=1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:44]=[CH:43][CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH:28][CH3:29])[CH2:22][CH2:21]3)[CH:15]=2)[N:12]=[C:11]([C:37]([F:38])([F:39])[F:40])[CH:10]=1)=[O:8]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCN1CCC(c2cccc(-n3nc(C(F)(F)F)cc3C(=O)NCc3ccccc3OC)c2)CC1
Temperature: 21 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a stirred solution of 70 (20 mg, 0.032 mmol) in CH2Cl2 (650 μl) was added TFA (50 μl, 0.650 mmol). The resulting solution was allowed to stir at 21° C. for 1.5 h. After the usual work-up, the residue was purified by preparative TLC using 10% MeOH/CH2Cl2. The title product 71 (16 mg, 79% yield) was isolated as a white solid. 1H NMR (CD3OD) δ(ppm): 7.38-7.36 (m, 3H), 7.27-7.24 (m, 2H), 7.14 (s, 1H), 7.12 (s, 1H), 6.94 (d, 1H, J=8.0 Hz), 6.87 (t, 1H, J=7.2 HZ), 4.44 (s, 2H), 3.81 (s, 3H), 3.13 (t, 2H, J=5.6 Hz), 3.05 (d, 2H, J=11.6 Hz), 2.72 (s, 3H), 2.67 (t, 2H, J=6.0 Hz), 2.61-2.59 (m, 1H), 2.22 (td, 2H, J=2.8, 12.0 Hz), 1.83-1.77 (m, 4H). LRMS (ESI): calc. 515.6; found 516.8 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([CH:19]=[O:20])=[CH:5][CH:4]=1.[Mn]([O-])(=O)(=O)=[O:22].[K+]>CC(C)=O.O.CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([C:19]([OH:22])=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2c1oc1ccc([N+](=O)[O-])cc12
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(=O)O)c2c1oc1ccc([N+](=O)[O-])cc12
Temperature: 65 °C

Procedure:
4-methoxy-8-nitro-1-formyl dibenzo[b,d]furan (1.1 gm, 0.0034 mol) in acetone (5 ml) was heated to 60-70° C. for 10 min. To the above suspension was added dropwise a hot solution of potassium permanganate (1.07 gm, 0.0068 mol) in water:acetone (1:3) (15 ml) for 10 min. The reaction was heated to 60-70° C. for 10 min., cooled to room temperature and filtered. The residue washed with acetone and the filterate was extracted with 10% sodium hydroxide solution. Acidification, followed by filteration and washing of the precipitate yielded 4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxylic acid (0.6 gin) as white solid; mp: 178° C. (dec.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:29][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:31][CH:32]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccc(OCc4ccccc4)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 4-benzyloxybenzylchloride as described from compound 78. Purified by chromatography (dichloromethane) and isolated as a colourless oil.
Reaction SMILES: II.[CH2:3]([N:5]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=2)=[CH:8][C:7]([C:19]2[CH:20]=[C:21]([C:25]3([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])[CH2:28][O:27][CH2:26]3)[CH:22]=[CH:23][CH:24]=2)=[N:6]1)[CH3:4].[O-]S([O-])(=S)=O.[Na+].[Na+].[NH4+:45].[OH-]>C1COCC1>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]2[N:5]([CH2:3][CH3:4])[N:6]=[C:7]([C:19]3[CH:20]=[C:21]([C:25]4([NH:29][S:30]([CH2:33][C:34]([F:36])([F:35])[F:37])(=[O:31])=[O:32])[CH2:28][O:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)[CH:8]=2)=[CH:16][CH:15]=1)#[N:45]
Reactant: CCn1nc(-c2cccc(C3(NS(=O)(=O)CC(F)(F)F)COC3)c2)cc1Oc1ccc(C=O)cc1
Reactant: [NH4+]
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(C3(NS(=O)(=O)CC(F)(F)F)COC3)c2)cc1Oc1ccc(C#N)cc1
Reaction time: 7 h
Yield: 65 %

Procedure:
Iodine (17.5 mg, 0.069 mmol, 1.3 equiv) was added to a stirring biphasic solution of N-(3-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}oxetane-3-yl)-2,2,2-trifluoroethanesulfonamide (27 mg, 0.053 mmol, 1.0 equiv) in 1 mL THF and 0.53 mL of concentrated NH4OH (28% solution). After stirring for 7 hours, aqueous Na2S2O3 was added (1 mL of a 5% solution) and the reaction mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (0-60% ethyl acetate:hexanes) to give N-(3-{3-[5-(4-cyanophenoxy)-1-ethyl-1H-pyrazol-3-yl]phenyl}oxetane-3-yl)-2,2,2-trifluoroethanesulfonamide (17 mg, 0.034 mmol, 65% yield). HRMS Calc'd (M+1)+507.1308. Found: 507.1305. (400 MHz, 1H, δ-CDCl3) 1.45 (3H, t, J=7.2), 3.04 (2H, q, J=8.6), 4.10 (2H, q, J=7.2), 5.04 (2H, d, J=7.1), 5.16 (2H, d, J=7.1), 5.66 (1H, br s), 6.11 (1H, s), 7.22 (2H, d, H=8.6), 7.36 (1H, d, J=7.9), 7.51 (1H, t, J=8.0), 7.70 (2H, d, J=8.6), 7.80 (2H, m).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:15](=O)[CH3:16])[CH:7]=[N:8][C:9]=2[O:10][CH2:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:15]([NH:24][S@@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])[CH3:16])[CH:7]=[N:8][C:9]=2[O:10][CH2:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1
Reactant: CC(=O)c1cnc(OCC(F)F)c(C2CC2)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)F)c(C2CC2)c1
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (0.21 g, colorless oil) from 1-(5-cyclopropyl-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone (0.20 g, 0.82 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.Br>CCOC(C)=O>[O:2]=[C:3]1[NH:8][C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)=[CH:6][CH:5]=[CH:4]1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(OC)n3)nc12
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(=O)[nH]3)nc12
Temperature: 90 °C
Yield: 67.9 %

Procedure:
To a mixture of (R)-ethyl 5-(2-(6-methoxypyridin-2-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.46 g, 1.25 mmol) and acetic acid (3.0 g, 50 mmol) was added HBr (3.1 g, 12.5 mmol, 33% in acetic acid). The reaction mixture was heated at 90° C. for 2 hours. After cooling, the reaction was diluted with EtOAc, washed with water, saturated NaHCO3, and brine, then dried (MgSO4), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 4% MeOH/DCM to yield the desired product (0.3 g, 67% yield). MS (apci) m/z=354.1 (M+H).
Reaction SMILES: Cl[CH2:2][N:3]([C:10](=[O:13])[CH2:11][Cl:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N.[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][CH2:2][N:3]([C:10](=[O:13])[CH2:11][Cl:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:16]
Reactant: O=C(CCl)N(CCl)c1ccccc1
Reactant: CCO
Agent: N
Product: CCOCN(C(=O)CCl)c1ccccc1
Reaction time: 0.67 h

Procedure:
About 2208 g (48 moles) of anhydrous ethanol was added to the reaction mixture containing the N-chloromethyl-α-chloroacetanilide intermediate. The addition of ethanol to the haloacetanilide mixture was done over 40 minutes at temperatures ranging from 45°-84° C. At the end of the ethanol addition, about 66.3 g (3.9 moles) of gaseous ammonia was introduced to the reaction mixture through a dip tube at about 50°-60° C. When the pH of the reaction mixture was about 8-9, the addition of ammonia was stopped and the reaction was considered complete. This reaction gave a 98.6% conversion of the haloacetanilide intermediate to the N-ethoxymethyl-2-chloroacetanilide.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26]>COCCOC.[I-].[K+]>[CH3:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(OCCOCCOC)cc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (2.0 g, 12.04 mmol) in dry DME (50 mL) was added potassium carbonate (3.33 g, 24.07 mmol), potassium iodide (100 mg, 0.602 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (3.6 mL, 24.07 mmol). The mixture was stirred at reflux for 2 days. After being cooled to rt, the solids were removed by filtration and the solvent by evaporation in vacuo. The remaining crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 5:1) to afford the title compound (2.17 g, 67%): 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 2H), 6.93 (d, 2H), 4.33 (quart, 2H), 4.19 (t, 2H), 3.88 (t, 2H), 3.72 (t, 2H), 3.57 (t, 2H), 3.39 (s, 3H), 1.37 (t, 3H); DCI(NH3)-MS m/z 286 (M+NH4)+; HPLC RT (Method I) 4.14 min.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:20])[CH:3]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[C:19]2[CH:18]=[C:15]([C:16]#[N:17])[CH:14]=[CH:13][C:12]=2[O:11]1
Reactant: CC(C)(C#Cc1ccccn1)Oc1ccc(C#N)cc1
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=C(c2ccccn2)c2cc(C#N)ccc2O1

Procedure:
12 98 g of 4-[1,1-dimethyl-3-(2-pyridyl)-2-propynyloxy]benzonitrile were dissolved in 50 ml of 1,2-dichlorobenzene and heated at reflux for 5 hours. After cooling the mixture was evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2), ethyl acetate/petroleum ether (1:1) and ethyl acetate for the elution. There were obtained 6.5 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 106-108° C. after recrystallization from cyclohexane.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:15][C:16]1[C:17]([CH:22]([NH2:36])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[N:18][CH:19]=[CH:20][N:21]=1.CCN(C(C)C)C(C)C.C[CH2:47][O:48]C(C)=O.C(Cl)Cl>C(Cl)Cl.C(O)=O>[Cl:15][C:16]1[C:17]([CH:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][CH:28]=2)[NH:36][CH:47]=[O:48])=[N:18][CH:19]=[CH:20][N:21]=1
Reactant: CCOC(C)=O
Reactant: NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Agent: On1nnc2ccccc21
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=CNC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of formic acid. (0.38 mL, 9.6 mmol), EDC (1.84 g, 9.6 mmol) and HOBt (0.2 g, 1.3 mmol) in CH2Cl2 (25 mL) under nitrogen were added compound C-(3-chloropyrazin-2-yl)-C-(4-phenoxyphenyl)-methylamine (2.0 g, 6.4 mmol), followed by DIEA (2.2 mL, 12.8 mmol). The mixture was stirred for 16 h at rt. TLC (EtOAc/CH2Cl2, 1:1) showed no starting material. The reaction mixture was diluted with CH2Cl2 (75 mL), washed with water (3×50 mL) and dried (Na2SO4). Evaporation of solvent gave desired product, which was used for next step without any further purification. Yield: 1.85 g (84%). 1H NMR (CDCl3, 300 MHz) δ 6.61 (d, J=6.8 Hz, 1H), 6.70-6.99 (m, 4H), 7.16 (t, J=7.2 Hz, 1H), 7.27-7.32 (m, 4H), 8.29 (s, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.61 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:12])=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C1CCNCC1
Reactant: O=C(O)c1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Solvent: ClCCl
Product: O=C(O)c1c(Cl)ccc(S(=O)(=O)N2CCCCC2)c1Cl

Procedure:
2,6-Dichloro-5-chlorosulfonylbenzoic acid (960 mg.; 3.3 m moles) is added portion-wise to 1.95 g. (0.0165 mole) of piperidine in 15 ml. of dry methylene chloride, and the mixture heated to reflux for 1.5 hrs. The solvent and excess amine are removed under reduced pressure and the residue dissolved in 15 ml. of 2 N sodium hydroxide. The aqueous base solution is extracted (2×50 ml.) with ether and acidified with 6 N hydrochloric acid. The precipitated gum is filtered, dried and allowed to crystallize in hexane, 1.1 g., m.p. 145°-150° C. A small sample is recrystallized from acetonitrile, m.p. 142°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]O)=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.P(Br)(Br)[Br:30]>C(#N)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][Br:30])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: CC(=O)Nc1cccc(-n2nc(CO)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Nc1cccc(-n2nc(CBr)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Yield: 93.2 %

Procedure:
According to Scheme 7 Step 6: To a solution of N-(3-(4-(4-chlorobenzyl)-6-(hydroxymethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (500 mg, 1.25 mmol) in acetonitrile (20 mL) under nitrogen atmosphere was added phosphorus tribromide (176 μL, 1.87 mmol) dropwise and the mixture was refluxed for 90 min. The reaction mixture was diluted with 200 mL a saturated solution of NaHCO3 (200 mL) and the aqueous layer was extracted twice with DCM (200 mL). The organic layers were combined to be dried over MgSO4, filtered and concentrated under reduced pressure to afford N-(3-(4-(4-chlorobenzyl)-6-(bromomethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 13(A) (540 mg, 93%) as a yellow solid.