Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:32]3[C:27](=[CH:28][N:29]=[C:30]([NH:33][C:34](=[O:36])[CH3:35])[CH:31]=3)[CH2:26][O:25][C:21]=2[C:22]=1[O:23][CH3:24]>>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:9][O:10][C:17]1[CH:18]=[CH:19][C:20]2[C:32]3[C:27](=[CH:28][N:29]=[C:30]([NH:33][C:34](=[O:36])[CH3:35])[CH:31]=3)[CH2:26][O:25][C:21]=2[C:22]=1[O:23][CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(Cl)ccc2c1OCc1cnc(NC(C)=O)cc1-2
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Product: COc1c(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc2c1OCc1cnc(NC(C)=O)cc1-2
Yield: 60 %

Procedure:
Prepared as described in Example 18, Part H using (5)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-7-methoxy-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford (5)-tert-butyl(1-((2-acetamido-7-methoxy-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (112 mg, 0.089 mmol, 60% yield) as a brown oil. LCMS (ESI) m/e 486.2 [(M+H)+, calcd for C26H36N3O6 486.2]; LC/MS retention time (Method F): tR=0.91 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][CH2:36][CH2:37][C:38]#[N:39]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][CH2:35][CH2:36][CH2:37][C:38]#[N:39])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCCCBr
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCCCC#N)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 95.3 %

Procedure:
Using 0.75 g (1.66 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 4-bromo-butyronitrile (0.245 g, 1.66 mmol) and following the procedure of Example 42(b) afforded 0.82 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (3H, m), 1.4 (9H, s), 1.8 (4H, m), 2.05 (3H, m), 2.65 (2H, m), 3.2 (1H, m), 3.7 (1H, m), 4.1 (2H, m), 6.76 (1H, d), 6.92 (1H, s), 7.14 (2H, d), 7.2 (1H, s), 7.34 (1H, s), 7.86 (2H, d), 8.28 (1H, d)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)C.N1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:20])[N:14]=[CH:15][C:16]([C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:19])=[C:11]2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN1CCOCC1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1,4-dicarboxylic acid 1-tert-butyl ester (300 mg) in dimethylformamide (4 ml) was added 4-ethylmorpholine (492 ul), morpholine (172 ul), 1-hydroxybenzotriazole hydrate (204 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (223 mg) and the solution stirred at room temperature overnight. The solution was diluted with ethyl acetate (50 ml). The organic layer was then washed with 5% sodium hydrogen carbonate solution (2×10 ml) and water (2×20 ml). The organic layer was dried (MgSO4) and evaporated to give an off-white foam (107 mg) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH:35]=O)=[CH:10][C:11]=3[C:12]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.[NH2:37][C:38]([C:40]([NH2:42])=[S:41])=[S:39]>CS(C)=O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:35]4[S:39][C:38]5[N:37]=[C:35]([C:9]6[CH:8]=[CH:7][C:6]7[C:5]8[C:13](=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=8)[C:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=7[CH:10]=6)[S:41][C:40]=5[N:42]=4)=[CH:10][C:11]=3[C:12]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: NC(=S)C(N)=S
Solvent: CS(C)=O
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(-c3nc4sc(-c5ccc6c(c5)C(CCCCCCCCCC)(CCCCCCCCCC)c5cc(Br)ccc5-6)nc4s3)cc21
Temperature: 190 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
A mixture of 7-bromo-9,9-didecylfluorene-2carbaldehyde (example 2; 6.6 g, 12 mmol), dithiooxamide (rubeanic acid, 0.6 g, 5 mmol) and DMSO (4 mL) was heated in an oil-bath to a bath temperature of 190° C., held 1 hour and poured onto water. The mixture was extracted into toluene (200 mL). The toluene extract was washed with water, dried and concentrated. The resulting residue was chromatographed over alumina to get a mixture of product containing the aldehyde product. The mixture was rechromatographed over silica gel, and elution with toluene gave 0.9 g (15% yield) of the product which was recrystallized from a mixture of heptane and hexanes to get pure product 0.6 g, (10% yield), m.p. 150.8-152.7° C. Mass Spec.(m/z): 1186, 1188, 1190 (M+). Anal. Calcd. for C70H96Br2N2S2: C, 70.68%; H, 8.14%; N, 2.36%; S, 5.39%; Br, 13.44%. Found: C, 70.69%; H, 8.22%; N, 2.07%; S, 5.31%; Br, 13.67%.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[O:19]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][NH:22][C:21](=[O:30])[CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:27]3[CH2:26][CH2:25][C:24]4([O:19][CH2:20][C:21](=[O:30])[NH:22][CH2:23]4)[CH2:29][CH2:28]3)=[CH:4][C:5]=2[N:6]=1
Reactant: O=C1COC2(CCNCC2)CN1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COC2(CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)CN1
Yield: 82.2 %

Procedure:
A solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (500 mg, 1.43 mmol), 1-oxa-4,9-diaza-spiro[5.5]undecan-3-one (315 mg, 1.85 mmol) and potassium carbonate (450 mg, 3.26 mmol) in DMF (40 mL) was stirred at ambient temperature for 18 hours, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH 100:0 to 98:2 to 95:5) to afford the title compound as a white solid (515 mg, 82%). LCMS (Method A): RT=2.51 min, [M+H]+ 438.1
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:19]([O:23][C:24]([N:26]([CH2:28][C:29](O)=[O:30])[CH3:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]([CH2:28][C:29]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:30])[CH3:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: COc1cccc(Cn2cnc(N)c2C(N)=O)c1
Product: COc1cccc(Cn2cnc(NC(=O)CN(C)C(=O)OC(C)(C)C)c2C(N)=O)c1
Yield: 63 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 1.97 g (8.00 mmol) of 4-amino-1-(3-methoxybenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 81 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 2.12 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(3-methoxybenzyl)-5-imidazolecarboxamide (yield 63%).
Reaction SMILES: C([O:4][C@H:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@@H:15]3[CH3:27])[C:8]=2[C@H:7]([CH3:28])[CH2:6]1)(=O)C.[Li+].[OH-]>C1COCC1>[OH:4][C@H:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@@H:15]3[CH3:27])[C:8]=2[C@H:7]([CH3:28])[CH2:6]1
Reactant: CC(=O)O[C@@H]1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.1 %

Procedure:
To a solution of the (S)-tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.281 g, 0.72 mmol) in THF (5 mL) was added LiOH (3M, 2 mL). The mixture was stirred at room temperature for 6 hours and then quenched with 2N HCl (3 mL). The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to give (S)-tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.206 g, 82%). 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 5.12 (m, 1H), 4.76 (br, 1H), 4.30-3.80 (m, 3H), 3.52 (m, 1H), 3.26 (m, 1H), 3.03 (br, 1H), 2.20 (m, 1H), 1.49 (s, 9H), 1.30-1.10 (m, 6H). MS (APCI+) [M+H] +349.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH:20]1[C:24]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])=[N:23][N:22]=[N:21]1>>[F:19][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)=[N:7][C:2]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:25]([C:24]3[NH:23][N:22]=[N:21][N:20]=3)[CH:26]=2)=[N:3][CH:4]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Fc1cnc(Nc2cccc(-c3nnn[nH]3)c2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with 3-(tetrazol-5-yl)aniline gave 5-fluoro-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.91 (s, 1H), 9.74 (s, 1H), 8.29 (s, 1H), 8.18 (d, 1H, J=4.5 Hz), 7.76 (bdd, 1H, J=1.5 and 8.1 Hz), 7.64 (d, 1H, J=8.1 Hz), 7.46 (t, 1H, J=8.1 Hz), 7.29 (m, 1H), 7.13 (dd, 1H, J=2.4 and 8.7 Hz), 6.64 (d, 1H, J=8.7 Hz), 4.11 (m, 4H); LCMS: purity: 91%; MS (m/e): 407 (MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[O:9])[CH2:2]1.[CH3:15][N:16]=[C:17]=[O:18]>>[CH3:15][NH:16][C:17]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[O:9])[CH2:2]1)=[O:18]
Reactant: CN=C=O
Reactant: NC(=O)c1ccccc1OC1CNC1
Product: CNC(=O)N1CC(Oc2ccccc2C(N)=O)C1

Procedure:
The compound was prepared from 2-(3-azetidinyloxy) benzamide and methylisocyanate as described in Example 2 of U.S. Pat. No. 4,226,861, m.p. 236°-240° C.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][CH:15]=[N:14][C:13]=1[CH3:17])[C:3]([OH:5])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[F:48][C:49]1[CH:50]=[C:51]([CH:67]=[CH:68][CH:69]=1)[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]2[S:64][C:63]([CH2:65][NH2:66])=[N:62][N:61]=2)=[CH:56][CH:55]=1>CN(C)C=O>[F:48][C:49]1[CH:50]=[C:51]([CH:67]=[CH:68][CH:69]=1)[CH2:52][O:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]2[S:64][C:63]([CH2:65][NH:66][C:3](=[O:5])[CH:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]3[S:16][CH:15]=[N:14][C:13]=3[CH3:17])=[N:62][N:61]=2)=[CH:58][CH:59]=1
Reactant: Cc1ncsc1CCCCCCC(O)C(=O)O
Reactant: NCc1nnc(-c2ccc(OCc3cccc(F)c3)cc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncsc1CCCCCCC(O)C(=O)NCc1nnc(-c2ccc(OCc3cccc(F)c3)cc2)s1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-hydroxy-8-(4-methylthiazol-5-yl)octanoic acid (40.0 mg, 0.155 mmol), 1-hydroxybenzotriazole hydrate (21.0 mg, 0.155 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (44.7 mg, 0.233 mmol), triethylamine (0.06 mL, 0.466 mmol) and (5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methanamine (54.7 mg, 0.155 mmol) in dimethylformamide (0.78 mL) was stirred at room temperature for 22 h. The resulting mixture was concentrated and the residue was purified via silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-80:20 heptane:EtOAc) to yield N-((5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)-2-hydroxy-8-(4-methylthiazol-5-yl)octanamide. MS (ES+) 555 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][C:8]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:7]2
Reactant: C1CCNC1
Reactant: O=C1CCc2cccc(Br)c2C1
Solvent: Cc1ccccc1
Product: Brc1cccc2c1CCC(N1CCCC1)=C2

Procedure:
To a solution of 8-bromo-2-tetralone (10 gm, 44.4 mMol) in toluene (175 ml) was added pyrrolidine (6.6 ml), and the solution was stirred at reflux for three hours. The volatiles were removed in vacuo to give 8-bromo-3-pyrrolidino-1,2-dihydronaphthalene as a brown oil. To this oil in p-dioxane (60 mL) was added methyl iodide (20 mL, 322 mMol), and the resulting solution was stirred at reflux for eighteen hours. The reaction mixture was diluted with water (60 mL) and acetic acid (3.2 mL), and heating was continued for an additonal three hours. After this time the solution was cooled to room temperature and the volatiles removed in vacuo. The residue was suspended in water and extracted well with diethyl ether. The organic phases were combined, washed with saturated aqueous NaHCO3, dried with Na2SO4 and concentrated in vacuo to give an orange oil. Purification by flash chromatography (33% diethyl ether in hexane) gave the title compound as a light orange oil (6.88 gm, 65%).
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[C:21](=O)[CH2:20][CH2:19][CH2:18]2>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH:21]([NH2:10])[CH2:20][CH2:19][CH2:18]2
Reactant: COc1cccc2c1C(=O)CCC2
Reactant: NC1CCCc2occc21
Product: COc1cccc2c1C(N)CCC2

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 8-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.13, 6.73, 4.21, 3.87, 2.78-2.72, 1.88; HRMS (FAB) calcd for C11H15NO+H 178.1232, found 178.1232.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([NH:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[N:7]=[C:6]([NH:18][C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[CH:20][CH:19]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:16][CH:15]=1)(=[O:12])[CH3:11]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(=O)Nc1ccc(N)cc1
Product: CC(=O)Nc1ccc(Nc2ncc(F)c(Nc3ccc(NC(C)=O)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-acetamidoaniline gave N2,N4-bis-(4-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 14.82 min.; purity: 95%; MS (m/e): 395 (MH+); 1H NMR (DMSO-d6): δ 10.33 (1H, s), 10.14 (1H, s), 10.07 (2H, s), 8.39 (1H, d, J=5.1 Hz), 7.64 (8H, m), 2.15 (3H, s), 2.13 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:46][C:47]([NH2:50])([CH3:49])[CH3:48]>CN(C=O)C.C(OCC)(=O)C>[C:47]([NH:50][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=1)=[O:23])([CH3:49])([CH3:48])[CH3:46]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: CC(C)(C)N
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Yield: 112.7 %

Procedure:
To a stirred suspension of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (111 mg, 242 μmol) in DMF (4 mL) was added EDC (107 mg, 557 μmol), HOBT (107 mg, 557 μmol) and 2-methylpropan-2-amine (78.6 mg, 0.113 mL, 1.08 mmol) at 20° C. After 3 h the reaction mixture was diluted with ethyl acetate and washed with 10% citric acid solution. The organic layer was then washed with saturated sodium bicarbonate and brine then dried (sodium sulfate), filtered and concentrated in vacuo to give the crude N-tert-butyl-2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg) as a light brown oil. This was used directly in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].O>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:4][C:3]([CH2:2][N:19]3[C:18](=[O:20])[C:17]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]4[C:15]3=[O:25])=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ncc(-c2ccc(Cl)cc2)o1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ncc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A suspension of 2.3 g of 2-chloromethyl-5-(4-chlorophenyl) oxazole and 1.94 g of potassium phthalimide in 15 ml of dimethylformamide was stirred at room temperature for 1 hour. The reaction mixture was poured into 300 ml of water, and the resultant precipitate was filtered and recrystallized from ethanol to give 2.4 g (71 percent) of N-[5-(4-chlorophenyl)-2-oxazolyl]methylphthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:17]2[N:22]=[C:21]([Br:23])[CH:20]=[CH:19][CH:18]=2)([C:10]2[N:15]=[C:14]([Br:16])[CH:13]=[CH:12][CH:11]=2)O)[N:3]=1.C(N(S(F)(F)[F:30])CC)C.[OH-].[Na+]>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:17]2[N:22]=[C:21]([Br:23])[CH:20]=[CH:19][CH:18]=2)([C:10]2[N:15]=[C:14]([Br:16])[CH:13]=[CH:12][CH:11]=2)[F:30])[N:3]=1
Reactant: OC(c1cccc(Br)n1)(c1cccc(Br)n1)c1cccc(Br)n1
Reactant: CCN(CC)S(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: FC(c1cccc(Br)n1)(c1cccc(Br)n1)c1cccc(Br)n1
Temperature: 5 °C

Procedure:
A solution of 50.0 g (100 mmol) of tris(2-bromo-6-pyridyl)methanol in 750 ml of dichloromethane was admixed with good stirring dropwise with 47.3 ml (400 mmol) of diethylaminosulfur trifluoride. Subsequently, the reaction mixture was heated under reflux for 30 min, then cooled to 5° C., and admixed with good stirring (highly exothermic!!!) with 300 ml of water and then with a solution of 64.0 g (1600 mmol) of sodium hydroxide in 600 ml of water (highly exothermic!!!). The organic phase was removed, the aqueous phase was washed twice with 200 ml of dichloromethane, and the combined organic phases were dried over calcium chloride and subsequently freed of dichloromethane. The remaining red-brown crystal slurry was taken up in 100 ml of methanol and filtered off. After washing with methanol, the colorless to beige crystals were dried under reduced pressure. The yield was 47.4 g (91.3%) at a purity of greater than 99.0% by 1H NMR.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C@H:10]([O:22][CH3:23])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:19]1([CH2:18][N:15]2[CH2:14][CH2:13][N:12]([CH2:11][C@@H:10]([O:22][CH3:23])[CH2:9][NH2:8])[CH2:17][CH2:16]2)[CH2:20][CH2:21]1
Reactant: [H][H]
Reactant: CO[C@H](CN1CCN(CC2CC2)CC1)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CO[C@@H](CN)CN1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 106.9 %

Procedure:
(2S)—N,N-Dibenzyl-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-methoxy-propan-1-amine 35c (500 mg, 1.23 mmol) was dissolved in 30 mL of methanol followed by the addition of palladium/carbon (100 mg, 10%), filled with hydrogen for three times. The reaction mixture was stirred at room temperature for 12 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (2S)-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-methoxy-propan-1-amine 35d (299 mg) as a yellow oil liquid, which was used in the next step without further furification.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][N:21]=1.C(=O)(O)[O-].[Na+]>C(O)CCC>[N+:26]([C:24]1[CH:23]=[CH:22][N:21]=[C:20]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:12][CH:13]=3)[CH2:3][CH2:4]2)[CH:25]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CS(=O)(=O)Nc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CS(=O)(=O)Nc1ccc(N2CCN(c3cc([N+](=O)[O-])ccn3)CC2)cc1
Reaction time: 24 h

Procedure:
A mixture of the product of (iii) above (1.46 g), 2-chloro-4-nitropyridine (0.79 g) and sodium bicarbonate (1.26 g) in n-butanol (30 ml) were heated under reflux with stirring for 24 hours and then cooled and filtered. The solid was washed with methanol and the combined filtrate and washings were evaporated to give a gum that was chromatographed on silica gel. Elution with dichloromethane, gradually increasing the polarity to dichloromethane/methanol (4:1) gave a mixture of the desired product, together with some N-{4-[4-(2-chloropyrid-4-yl)piperazin-1-yl]phenyl}methanesulphonamide biproduct, as a solid. The solid was crystallised four times from methanol to give pure N-{4-[4-(4-nitropyrid-2-yl)piperazin-1-yl]phenyl}methanesulphonamide (0.36 g), m.p. 182°-183° C. Found: C,50.90; H,5.07; N,18.51. C16H19N5O4S requires: C,50.91; H,5.07; N,18.56%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[C:19]([CH3:24])=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:33]=[C:32]([N:34]=[C:35]=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:33]=[C:32]([NH:34][C:35]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[C:22]4[NH:21][C:20](=[O:23])[C:19]([CH3:24])=[N:18][C:17]=4[N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1nc2nccc(Oc3ccc(N)c4ccccc34)c2[nH]c1=O
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: Cc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c4ccccc34)c2[nH]c1=O
Yield: 41 %

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-3-methylpyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a white solid (50 mg, 41%).