Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][NH:24][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: OCCCSc1ccncc1
Reactant: NCc1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(CNCCCSc2ccncc2)nc1
Temperature: 80 °C
Yield: 24.4 %

Procedure:
To a solution of 5.26 g (31.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.20 ml (37.3 mmol) of triethylamine in 150 ml of methylene chloride, 2.90 ml (37.3 mmol) of methanesulfonyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. To 6.33 g of the residue was added 2.64 ml (25.6 mmol) of 2-aminomethylpyridine. The resulting mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 1.62 g of the desired compound (yield: 25.4%, yellow oil).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]([N:16]([CH3:28])[C:17](=[O:27])[CH:18]=[C:19]2[C:23](=O)[O:22]C(C)(C)[O:20]2)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C=O.[CH3:33][NH2:34].[CH3:35]O>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:7]([N:16]([CH3:28])[C:17]([C:18]2[CH2:33][N:34]([CH3:35])[C:23](=[O:22])[C:19]=2[OH:20])=[O:27])[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:30][CH:29]=2)=[CH:14][CH:13]=1
Reactant: CN(C(=O)C=C1OC(C)(C)OC1=O)C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reactant: CN
Reactant: CO
Agent: C=O
Product: CN1CC(C(=O)N(C)C(Cc2ccc(Cl)cc2)Cc2ccc(Cl)cc2)=C(O)C1=O
Yield: 56 %

Procedure:
N-[1-(4-Chloro-benzyl)-2-(4-chloro-phenyl)-ethyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation of Compound 44, Method 44B, to give the title compound as white crystals (56% yield); mp 152–154° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): mixture of rotamers: 2.7–3.0 (4H, m, CH2), 2.84 (3H, s, NCH3), 2.9 (3H, broad s, NCH3), 3.4 and 3.7 (2H, two broad s, NCH2), 4.16 and 4.9 (1H, broad m, CH), 7.15–7.34 (8H, m, aromatics), 10.7 and 11.0 (1H, two s, OH). HRMS (MAB N2) calculated for C22H22Cl2N2O3: [M]+: 432.100748. found: 432.100835.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[C:41](O)=[O:42])(=[O:35])[CH3:34].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[C:41]([N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:42])(=[O:35])[CH3:34]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: CC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC[C@@H]1C(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), (R)-acetyl-pyrrolidine-2-carboxylic acid (35 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (65 mg). MS found for C31H34F2N6O3 as (M+H)+ 577.5. UV: λ=259 nm. 1H NMR (a pair of rotomers): (CD3OD) δ 8.13 (with 8.15, 1H, s), 7.36 (with 7.32, 2H, d, J=8.8 Hz), 7.25 (1H, m), 7.16 (1H, m), 7.13-7.07 (3H, m), 5.83 (with 5.79, 1H, s), 4.95 (1H, m), 4.65 (1H, m), 4.56 (with 4.55, 2H, s), 4.20 (1H, m), 3.66 (2H, m), 3.30 (1H, m), 2.92 (1H, m), 2.79 (1H, m), 2.27 (1H, m), 2.12 (with 2.10, 3H, s), 2.07-1.85 (5H, m), 1.68 (2H, m) ppm.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])(C)(C)C.[C:18]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CO.CN(C=O)C>[C:21]([O:20][C:18](=[O:19])[NH:25][CH2:26][CH2:27][CH2:28][C:29](=[O:31])[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CCNC(=O)CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)CCCNC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrochloric acid (12%, 64 ml) was added to a cold solution of Boc-derivative 3 (21.1 g, 91.7 mmol) in MeOH (190 ml) and stirred overnight at room temperature. The next day additional acid (30 ml) was added and stirring was continued for another 10 h. The reaction mixture was filtered, washed with CHCl3, concentrated and dried in vacuo overnight. The product was suspended in DMF (300 ml) with DIEA (42 ml), cooled to 0° C. and a solution of Bt-derivative 2 (29 g, 90.5 mmol) in DMF (100 ml) was added into the reaction mixture. The cooling bath was removed and the stirring was continued overnight. The solvent and DIEA were removed in vacuo at 45° C., the residue was suspended in CHCl3/H2O mixture, washed with H2O, aq. KHSO4 (20%), H2O, aq. NaHCO3 (2 times with each), dried (Na2SO4), concentrated in vacuo, and triturated with petr. ether. Yield 22.32 g (78%). mp: 134-1350. 1H (CDCl3): 1.15 (t, J=7.27, 3H), 1.44 (s, 9H), 1.65-1.95 (m, 4H), 2.20-2.26 (m, 4H), 3.19 (q, J=6.15, 2H), 3.23-3.35 (m, 4H), 4.82 (bs, 1H), 6.40 (bs, 1H), 6.68 (bs, 1H). 13C (CDCl3): 14.77, 24.92, 25.66, 26.43, 28.38, 33.59, 33.84, 33.92, 34.35, 38.83, 39.66, 79.35, 156.56, 172.65, 173.12. ESI-MS: 338.2 (MNa+), 316.0 (MH+), 216.0 (MH+-Boc).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1.CCCCCC.[Li]CCCC.[CH3:28][C:29](N(C)C)=[O:30]>CCOCC.C1COCC1>[C:29]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1)(=[O:30])[CH3:28]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-Bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (1.59 g, 5.26 mmol) in a mixture of ether, hexane and THF (2:1:1, 105 mL) was added n-BuLi (3.29 mL, 5.26 mmol, 1.6 M in hexane solution) dropwise at −78° C. during 5-10 min. To the resulting dark brown solution was dropped anhydrous DMA (0.74 mL, 7.89 mmol) at the same temperature. The reaction mixture was stirred for 30 min and then quenched with water (8 mL) and extracted with EtOAc. The organic layer was washed with water and brine and dried over MgSO4. After purification by column chromatography on silica gel (hexane/EtOAc 98:2) 0.78 g (56%) of the title compound as an oil were obtained. 1H NMR (CDCl3) δ 7.95 (d, 1H, J=7.5 Hz, H-3), 7.88 (t, 1H, J=7.6 Hz, H-4), 7.73 (t, 1H, J=7.6 Hz, H-5), 4.93 (s, 2H, CH2), 2.75 (s, 3H, CH3), 1.03 (s, 9H, (CH3)3C), 0.20 (s, 6H, (Me)2Si); 13C NMR (CDCl3) δ 200.8 (CO), 161.4 (C-6), 153.0 (C-2), 139.4 (C-4), 124.0 (C-5), 118.0 (C-3), 66.4 (CH2), 26.3 ((CH3)3C), 18.8 ((CH3)3C), -4.96 ((Me)2Si).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH3:20])[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:24][CH3:23])[C:12]=2[O:19][CH3:20])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1OC
Yield: 77.3 %

Procedure:
4-Chloro-2-(3-formyl-2-methoxy-phenoxy)-benzonitrile (0.52 g, 1.8 mmol), methylamine (2M in methanol, 2.7 ml, 5.4 mmol) and sodium cyanoborohydride (0.13 g, 2.1 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (70 ml) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. Fumaric acid (0.21 g, 1.8 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(2-methoxy-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (583 mg, 77%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C@H:15]([C:16]([OH:18])=O)[C@@H:14]([C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:13][N:12]2C(OC(C)(C)C)=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH2:35]([OH:37])[CH3:36]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[C@H:15]([C:16]([O:37][CH2:35][CH3:36])=[O:18])[C@@H:14]([C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:13][NH:12]2)=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc([C@H]2[C@H](C(=O)O)[C@@H](c3ccc4c(c3)OCO4)CN2C(=O)OC(C)(C)C)cc1
Reactant: CCO
Product: CCCOc1ccc([C@@H]2NC[C@H](c3ccc4c(c3)OCO4)[C@H]2C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 20A was dissolved in ethanol and cooled in an ice bath. Gaseous HCl was bubbled through the solution until saturated; the resultant solution was warmed to ambient temperature and allowed to stir overnight under a blanket of nitrogen. The solvents were removed in vacuo; the residue was taken up in bicarb and extracted with EtOAc. The organic layer was decanted, then washed with brine and dried over Na2SO4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[CH:9](O)([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1
Reactant: CC(C)O
Reactant: Oc1ccc(Br)nc1
Product: CC(C)Oc1ccc(Br)nc1

Procedure:
The title compound was prepared from 2-bromo-5-hydroxypyridine and isopropanol in analogy to Example 9c): MS (EI): 215 and 217 M+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][Cl:20])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])#[CH:22]>>[ClH:1].[Cl:20][CH2:19][CH2:18][O:17][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([C:21]#[CH:22])[CH:24]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1cc2c(Cl)ncnc2cc1OCCCl
Reactant: C#Cc1cccc(N)c1
Product: C#Cc1cccc(Nc2ncnc3cc(OCCCl)c(OCCOC)cc23)c1
Product: Cl

Procedure:
This product was prepared from 4-chloro-7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazoline (600 mg, 1.89 mmol) and 3-ethynyl-aniline (147 mg, 1.26 mmol) as described for Example 29. (737 mg; 90%; M.P. 225°-235° C. (dec); LC-MS: 398 (MH+); anal. RP18-HPLC RT: 4.89 min.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:23])[C:9]1[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[O:21][CH3:22].[C:24]1(=O)[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:1][CH:2]2[CH2:6][CH2:5][CH2:4][CH:3]2[NH:7][C:8](=[O:23])[C:9]2[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:19])([F:20])[F:18])=[CH:11][C:10]=2[O:21][CH3:22])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CCC1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC1CCC1

Procedure:
The title compound, white solid, MS: m/e=403.4 [(M+H)+], was prepared in accordance with the general method of example 11 from N-((1RS,2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and cyclobutanone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[C:20]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:33]1[CH2:32][CH2:31][N:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:35][CH2:34]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: O=CCCCOc1nc2c(cc1Cl)CCC(=O)N2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1CCc2cc(Cl)c(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
To a solution of 4-(3-chloro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (400 mg, approx. 1.49 mmol, crude from previous reaction) in DCE (7 mL) was added 1-naphthalen-1-yl-piperazine hydrochloride (370 mg, 1.49 mmol) followed by Et3N (0.42 mL, 2.98 mmol). The solution was stirred for 15 min and NaBH(OAc)3 (410 mg, 1.94 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (0–3% MeOH/CH2Cl2) afforded the title compound as an off-white foam (324 mg, 0.697 mmol, 47%). Et2O was added and the foam turned into a white solid after 5 minutes of stirring. The solid was collected by filtration, washed with Et2O and dried to give a white solid. MS: APCI: M+1: 465.2 (Exact Mass: 464.20).
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+:14]=[N-:15]>>[ClH:1].[CH3:25][C:17](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][N:13]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]2[NH:8][C:9]([NH2:12])=[N:10][CH:11]=2)[N:15]=[N:14]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCc2cnc(N)[nH]2)nn1
Yield: 41 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.096 g, 0.517 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.110 g, 0.635 mmol) following the general procedure for click reactions outlined above to produce 5-{3-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imidazol-2-ylamine hydrochloride (0.076, 41%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.65 (s, 1H), δ 7.14-7.04 (m, 5H), δ 6.35 (s, 1H), δ 6.28 (s, 1H), δ 4.94 (s, 2H), δ 2.57 (t, 2H), δ 2.34 (t, 2H), δ 1.75 (m, 2H), δ 1.57 (s, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.5, 136.9, 132.5, 129.7, 128.8, 128.6, 128.4, 128.3, 128.2, 126.9, 122.5, 109.2, 58.1, 61.9, 28.0, 24.3, 24.3, 24.1, 14.6 ppm; HRMS (ESI) calcd for C18H22N6 (M+) 323.1978. Found 323.1984.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[C:27]([CH:28]=O)=[N:26][N:25]=[N:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:27]4[NH:26][N:25]=[N:24][N:23]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1nnn[nH]1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4nnn[nH]4)c23)c1
Reaction time: 8 h

Procedure:
With gentle heating, 195 mg (0.75 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 135 mg of acetic acid are dissolved in 20 ml of methanol. Then, at RT, 1.0 mmol of tetrazole-5-carbaldehyde is added and the reaction mixture is stirred overnight to complete the reaction, during which a solid separates out. Concentration by evaporation to approximately half volume and filtration yield 4-(3-chloro-phenylamino)-3-[(tetrazol-5-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. More material can be recovered from the mother liquor by concentration by evaporation and stirring the residue in isopropanol. Under a nitrogen atmosphere, 208 mg of the above intermediate are dissolved in 27 ml of DMEU and, with ice cooling, 4.2 ml (4.2 mmol) of DIBAL-H are added and the mixture is stirred for 7 hours. 13 ml of ethyl acetate are added and the mixture is stirred for 30 min and diluted with 130 ml of methanol. 0.9 ml of water and 9 g of Na2SO4 are added to the precipitate, followed by stirring for 30 min and then filtration. The filtrate is concentrated by evaporation (RV, HV) and chromatographed (SiO2; CH2Cl2/−methanol=4:1) and the crude product is stirred in isopropanol/diethyl ether to yield 4-(3-chloro-phenylamino)-3-[(tetrazol-5-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine:HPLC: tRet(grad20-100)=6.7; FAB MS (M+H)+=343.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:32])=[C:5]([F:31])[CH:6]=[C:7]2[C:12]=1[N:11]([C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH:22]([CH3:24])[CH3:23])[N:14]=1)[CH:10]=[C:9]([C:25]([O:27]CC)=[O:26])[C:8]2=[O:30]>C(O)(=O)C>[Cl:2][C:3]1[C:4]([F:32])=[C:5]([F:31])[CH:6]=[C:7]2[C:12]=1[N:11]([C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH:22]([CH3:24])[CH3:23])[N:14]=1)[CH:10]=[C:9]([C:25]([OH:27])=[O:26])[C:8]2=[O:30]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Yield: 94.1 %

Procedure:
To 3 ml of the mixed solution of 4N hydrochloric acid and acetic acid (1:1, v/v) was added 300 mg of ethyl 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-isopropylaminopyridine-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux for 19 hours with stirring. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 265 mg of the title compound as a yellow powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O1CCCC1>O1CCCC1.O.CCCCCCC>[CH2:19]([O:18][C:16](=[O:17])[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=C(NCc1ccc(O)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To a stirred solution of 4-aminomethylphenol (1 g, 8.13 mmol) in tetrahydrofuran/water (1:1 ratio, 20 ml) at 0° C. was added solid NaHCO3 (0.888 g, 10.16 mmol) followed by dropwise addition of benzyl chloroformate (1.16 ml, 8.13 mmol). The mixture was stirred at 0° C. for 10 minutes then allowed to warm slowly to r.t. After stirring the mixture for 90 minutes the tetrahydrofuran was removed in vacuo. The aqueous layer was extracted with EtOAc (2×10 ml). The organic layer was washed with water (2×10 ml), dried (MgSO4), and the solvent removed in vacuo to a residue. Trituration with heptane gave the product as a white solid (2.10 g, 100% yield). LCMS purity 100%, m/z 258 [M++H]−.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=3)[NH2:12])[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C)C1C=CN=CC=1.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([NH:12][S:31]([CH3:30])(=[O:33])=[O:32])[CH:13]=[CH:14][CH:15]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of 3-(6-bromobenzoxazol-2-yl)aniline (Compound of Example 267) (925 mg), triethylamine (490 mg), 4-dimethylaminopyridine (39 mg) and tetrahydrofuran (35 ml) was added methanesulfonyl chloride (440 mg) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, successively, and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain N-[3-(6-bromobenzoxazol-2-yl)phenyl]methane sulfonamide (686 mg, 58%). The crystals were recrystallized from ethyl acetate-hexane.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[N:7][CH:8]=1)#[N:2].O.O.[Sn](Cl)Cl>C(O)C>[NH2:16][C:12]1[CH:11]=[C:10]([NH:9][C:6]2[N:5]=[C:4]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cnc(Nc2cccc([N+](=O)[O-])c2)nc1-c1cccs1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: N#Cc1cnc(Nc2cccc(N)c2)nc1-c1cccs1

Procedure:
N-3-Aminophenyl-5-cyano-4-thien-2-ylpyrimidine-2-amine was prepared by heating a solution of 5-cyano-N-3-nitrophenyl-4-thien-2-ylpyrimidine-2-amine (2.77 g, 8.57 mmol) and tin(II)chloride dihydrate (7.73 g, 34.05 mmol) in ethanol (160 mL) at reflux for 18 h. On cooling the reaction was concentrated under reduced pressure and partitioned between CH2Cl2 and 2M NaOH. The organic phase was dried (MgSO4) and evaporated to give the desired material (320 mg) as a yellow solid, m.p. 221-222°. δH (d6 DMSO) 10.16 (1H, s), 8.83 (1H, s), 8.24 (1H, d, J 3.9 Hz), 7.97 (1H, d, J 5.1 Hz), 7.32 (1H, dd, J 5.0, 4.0 Hz), 6.97 (3H, bm), 6.31 (1H, m) and 5.04 (2H, bs).