Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH:15]=[CH2:16])[CH:8]=1)[CH3:2].Br[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[C:9]([CH2:14][CH:15]=[CH2:16])[CH:8]=1)[CH3:2]
Reactant: BrCCCOc1ccc(Oc2ccccc2)cc1
Reactant: C=CCc1cc(C[C@H](OC)C(=O)OCC)ccc1O
Product: C=CCc1cc(C[C@H](OC)C(=O)OCC)ccc1OCCCOc1ccc(Oc2ccccc2)cc1

Procedure:
(2S)-3-(3-Allyl-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester from Step A was allowed to react with 4-(3-bromopropoxy)-1-phenoxybenzene under the Standard Procedure I to give the title compound.
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C12C(C3C=CC(O)=CC=3)C(CCC1)CCC2.C1O[C@H]1CCl.C([O:47][C:48](=O)[C:49]#[C:50][CH2:51][F:52])C>C(O)(C)(C)C>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:48](=[O:47])[CH:49]=[C:50]([CH2:51][F:52])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Reactant: CCOC(=O)C#CCF
Agent: ClC[C@H]1CO1
Agent: Oc1ccc(C2C3CCCC2CCC3)cc1
Solvent: CC(C)(C)O
Product: O=c1cc(CF)n2c(n1)O[C@H](COc1ccc(C3C4CCCC3CCC4)cc1)C2
Yield: 123.5 %

Procedure:
To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-yl-amine (1.1 g, 3.5 mmol) (prepared from 4-bicyclo[3.3.1]non-9-yl-phenol and R-epichlorohydrin employing the procedures in Steps 1 through 2 of Example 1) in t-butanol (13 mL) was added 0.82 g (0.63 mmol) of 4-fluoro-but-2-ynoic acid ethyl ester (prepared in accordance with the procedures as described in Poulter, J Org Chem 1981, 46, 1532). The reaction mixture was refluxed for 6 hours after which it was concentrated and loaded on silica gel column and eluted with 1-6% EtOH/CH2Cl2 to afford 0.31g of the title compound. [α]D25 −26.00 (c 0.5, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[N:13]([CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:22])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Product: CCOC(=O)Cn1cc(-c2ccc(OC)cc2)ccc1=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.6 %

Procedure:
According to Scheme 9 Step 1: The title compound was prepared from 5-(4-methoxyphenyl)pyridin-2(1H)-one (1 eq, 3.73 mmol, 0.75 g, Example 7 Step 1) and ethylbromoacetate (1.2 eq, 4.47 mmol, 0.50 mL) according to the procedure described for Example 1 Step 2. The reaction was stirred at 60° C. for 12 hours. The reaction was filtered and concentrated under reduced pressure to yield a yellow oil. The product was triturated from diisopropyl ether to afford ethyl 2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)acetate (3.38 mmol, 0.97 g, 91%) as a white solid.
Reaction SMILES: [BH4-].[Na+].C([C:5]1[CH:6]=[C:7]([C:16]#[C:17][C:18]2([OH:26])[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])=O.[CH3:27][OH:28]>>[OH:28][CH2:27][C:8]1[CH:9]=[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:6][C:7]=1[C:16]#[C:17][C:18]1([OH:26])[CH:23]2[CH2:22][CH2:21][N:20]([CH2:25][CH2:24]2)[CH2:19]1
Reactant: CO
Reactant: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Product: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)c(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium borohydride (28.4 mg) was added to a solution of 3-[2-(3-formyl-4-(2-methoxyethoxy)phenyl)ethynyl]quinuclidin-3-ol in methanol at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1.5 hours. The reaction mixture was poured onto water (15 ml) and the mixture extracted with ethyl acetate (3×20 ml). The ethyl acetate extracts were combined, washed with brine solution (20 ml), dried (MgSO4) and evaporated. The residue was dissolved in acetonitrile (5 ml) and diethylether was added to give, on cooling, a solid (262 mg). This solid was further purified by crystallisation from acetonitrile to give 3-[2-(2-hydroxymethyl-4-(2-methoxyethoxy)phenyl)ethynyl]quinuclidin-3-ol (217 mg) as a solid, m.p. 98.5-100.0° C.; microanalysis, found C, 67.5%; H, 7.7%, N, 6.9%, C19H25NO4 0.8CH3CN requires: C, 67.9%; H, 7.6%; N, 6.9%; NMR(CDCl3): 1.40(1H,m), 1.65(1H,m), 2.0(3H,s), 2.05(3H,m), 2.8(4H,t), 3.03(1H,d), 3.28(1H,d), 3.45(3H,s), 3.75(2H,t), 4.13(2H,t), 4.72(2H,s), 6.78(1H,m), 7.05(1H,d) and 7.3(1H,t); m/z 332(M+H).
Reaction SMILES: ClC1N=NC(C2C=CC=CC=2)=CC=1C1C=CN=CC=1.N1(CCN)CCOCC1.CN1CCN([C:36]2([NH:54][CH2:55][CH2:56][N:57]3[CH2:62][CH2:61][O:60][CH2:59][CH2:58]3)[C:41]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[CH:40][C:39]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[N:38][NH:37]2)CC1>>[O:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][NH:54][C:36]2[N:37]=[N:38][C:39]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:40][C:41]=2[C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)[CH2:58][CH2:59]1
Reactant: CN1CCN(C2(NCCN3CCOCC3)NN=C(c3ccccc3)C=C2c2ccncc2)CC1
Agent: Clc1nnc(-c2ccccc2)cc1-c1ccncc1
Agent: NCCN1CCOCC1
Product: c1ccc(-c2cc(-c3ccncc3)c(NCCN3CCOCC3)nn2)cc1
Temperature: 130 °C
Reaction time: 168 h

Procedure:
A mixture of 3-chloro-6-phenyl-4-(pyridin-4-yl)pyridazine (MW01-7-076WH) (0.5 mmol), 2-Morpholin-4-yl-ethylamine (2.0 mmol) in 3 ml of 1-BuOH was heated with stirring at 130° C. for about 7 days. The solvent was removed by evaporation in vacuo, the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, then 1:3, Ethyl Acetate:Petroleum ether, dried over filter funnel in vacuo to yield a gray solid. ESI-MS: m/z 362.2 (M+H+). A synthetic reaction scheme for the preparation of 3-(4-methylpiperazin-1-yl)-N-(2-morpholinoethyl)-6-phenyl-4-(pyridin-4-yl)pyridazin-3-amine (MW01-7-091WH) is depicted in FIG. 10.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:25]C(=O)OC(C)(C)C)([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][C:10]=3[CH:9]=2)[CH2:4][O:3]1.IC1C=C(CCCCCCCC)C=CC=1S.ClC1C=C(C2ON=C(C3C=CC(O)=C(I)C=3)N=2)C=CC=1OCCC>>[NH2:25][C:5]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][C:10]=2[CH:9]=1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCCCCCCc1ccc2sc(C3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2c1
Agent: CCCCCCCCc1ccc(S)c(I)c1
Agent: CCCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1Cl
Product: CCCCCCCCc1ccc2sc(C(N)(CO)CO)cc2c1
Yield: 24 %

Procedure:
tert-Butyl 2,2-dimethyl-5-(5-octylbenzo[b]thiophen-2-yl)-1,3-dioxan-5-ylcarbamate When with the product of Step B was substituted for 4-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-iodophenol in Example 36, Step D, the similar procedure afforded the title compound in 24% yield, as white solid. 1H NMR (CDCl3) 7.65 (d, 1H, J=8.16 Hz); 7.47 (s, 1H); 7.1 (d, 1H, J=6.18 Hz); 7.1 (s, 1H); 5.44 (b, 1H); 4.16 (b, 4H); 2.66 (t, 2H, J=7.5 Hz); 1.6-1.1 (m, 27H); 0.86 (t, 3H, J=6.18 Hz).
Reaction SMILES: [CH:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH:8]3[CH2:7][CH2:6][CH:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CCC(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C)C1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 85.5 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-sec-Butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol) and 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 152 mg of the desired product as a white solid (50%). ESI-MS: 339 (M−16)+. 1H NMR (400 MHz, DMSO-d6) δ=8.30 (s, 1H), 7.88 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71-7.56 (m, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.12 (dd, J=2.3, 8.8 Hz, 1H), 4.70 (d, J=5.8 Hz, 1H), 4.40-4.28 (m, 1H), 3.55-3.41 (m, 2H), 2.26-1.07 (m, 12H), 0.94-0.79 (m, 3H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([O:23][C:19]4[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=3)=[C:3]([C:15]#[N:16])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: Nc1ccc(Oc2cccnc2)cc1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Oc4cccnc4)cc3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 635.4 mg (2.68 mmol) 4-chloro-7-fluoro-6-methoxy-quinoline-3-carbonitrile, 500 mg (2.81 mmol) of 4-(pyridin-3-yloxy)phenylamine and 309.8 mg (2.68 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (27 mL) at 100° C. for 12 hours to yield 7-fluoro-6-methoxy-4-[4-(pyridin-3-yloxy)-phenylamino]-quinoline-3-carbonitrile as an off-white solid, mp 235-236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH2:19][C:20]4([OH:27])[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)[CH:17]=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[BH3-]C#[N:30].[Na+]>CO>[NH2:30][CH:23]1[CH2:24][CH2:25][C:20]([CH2:19][C:16]2[CH:17]=[CH:18][N:14]3[C:15]=2[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[N:11][CH:12]=[N:13]3)([OH:27])[CH2:21][CH2:22]1
Reactant: O=C1CCC(O)(Cc2ccn3ncnc(Nc4ccc(F)c(Cl)c4)c23)CC1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: NC1CCC(O)(Cc2ccn3ncnc(Nc4ccc(F)c(Cl)c4)c23)CC1
Reaction time: 12 h
Yield: 15 %

Procedure:
To a solution of 4-[4-(3-chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-4-hydroxy-cyclohexanone (24 mg, 0.06 mmole) in dry MeOH (0.5 mL) was added powdered 3 A molecular sieves (24 mg), (10 eq) NH4OAc (48 mg, 0.06 mmole), and NaCNBH3 (4 mg, 0.06 mmole); the reaction stirred under nitrogen for 12 hr. The reaction mixture was filtered and a 15% NaOH solution was added. After 10 min, the mixture was diluted with DCM (50 mL) and washed with water. The organic phase was dried (Na2SO4) and the solvent was removed. The material was purified and separated by preparative HPLC to afford the title compound (3.5 mg, 15%) and the cis isomer (7.9 mg, 32%). The title compound: MS: 390 (M+H)+; HPLC Ret Time: 2.070 min (XTERRA 4.6×50 mm S5 column, 3 min gradient, 4 mL/min). The cis isomer: MS: 390 (M+H)+; HPLC Ret Time: 2.190 min (XTERRA 4.6×50 mm S5 column, 3 min gradient, 4 mL/min).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:6][CH:7]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1O[C@H](c2ccccc2)CN1c1ccc(O)cc1
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(N2C[C@@H](c3ccccc3)OC2=O)cc1
Temperature: 0 °C
Yield: 30.1 %

Procedure:
Then, 0.30 g (1.18 mM) of (5R)-3-(4-hydroxyphenyl)-5-phenyl-2-oxazolidinone and 4.6 ml of DMF were placed in 30 ml-round bottomed flask, followed by stirring to form a solution. To the solution, 0.053 g (1.33 mM) of 60%-oily sodium hydride was added under stirring at room temperature. After the settlement of foaming, 0.25 ml (1.38 mM) of 1-iodooctane was added to the mixture, followed by stirring for 30 minutes on an oil bath kept at about 70° C. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by purification by silica gel column chromatography (eluent: toluene/ethyl acetate =100/1) and recrystallization from a toluene-methanol mixture solvent to obtain 0.13 g of (5R)-3-(4-octyloxyphenyl)-5-phenyl-2-oxazolidinone (Yield: 30.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([C:8]23[CH2:15][CH:14]2[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:9]3)[CH:7]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[Cl:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][N:30]=2)=[CH:7][C:6]=1[C:8]12[CH2:15][CH:14]1[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:9]2
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(N)ccc3Cl)CC2CCS1
Product: CC(C)(C)OC(=O)NC1=NC2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3Cl)CC2CCS1
Yield: 54.4 %

Procedure:
Prepared in an analogous manner as described for intermediate rac-A9a from tert-butyl (1SR,7SR)-1-(5-amino-2-chlorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate rac-A8b) (56 mg, 152 μmol) and 5-chloro-2-pyridinecarboxylic acid to give the tert-butyl (1SR,7SR)-1-(2-chloro-5-(5-chloropicolinamido)phenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (42 mg, 82.8 μmol, 54.4% yield) as a light brown oil. MS (ISP): m/z=407.2 [(M-Boc+H)+], 409.2 [(M-Boc+2+H)+] and 411.0 [(M-Boc+4+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:9]([C:11]3[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12.Br[C:32]1[C:33]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])=[CH:41][CH:40]=2)=[N:34][N:35]([CH2:37][CH3:38])[CH:36]=1>>[CH3:48][N:47]([CH3:49])[C:46]([NH:45][C:42]1[CH:41]=[CH:40][C:39]([C:33]2[C:32]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([S:22]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)(=[O:24])=[O:23])[C:9]([C:11]5[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=5)=[CH:10][C:3]=34)=[CH:36][N:35]([CH2:37][CH3:38])[N:34]=2)=[CH:44][CH:43]=1)=[O:50]
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CS(=O)(=O)Nc1cccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)c1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(NS(C)(=O)=O)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with N-{3-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanesulfonamide. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 684.4
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Br:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[N:15]=[C:16]=[O:17].O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[NH:15][C:16]([N:8]=[C:7]1[NH:6][C:4](=[O:5])[CH2:3][N:2]1[CH3:1])=[O:17]
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1sccc1Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1sccc1Br
Temperature: 65 °C
Yield: 20.7 %

Procedure:
To a stirred suspension of 0.8 g (7.1 mM) of creatinine in 10 ml of anhydrous DMF was added a solution of 1.12 g (5.5 mM) of 3-bromo-2-thienyl isocyanate in 5 ml of toluene. The resulting mixture was heated at 65° C. for 5 hrs. (hours), cooled, and poured into a mixture of 200 ml water and 25 ml toluene. The precipitate was collected and recrystallized from ethyl acetate to give 0.36 g of the above urea as a tan colored solid, m.p. 192°-193° C. (dec.)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH2:39])[CH:34]=[CH:35][C:36]=1[Cl:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH:39][C:24](=[O:26])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Reactant: NCc1ccc(Cl)c(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
In a 100 mL round-bottomed flask was added 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.0 g, 2.478 mmol), 1-(3-bromo-4-chlorophenyl)methanamine (0.595 g, 2.7 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.641 ml, 4.6 mmol) in dichloromethane (35 mL) to give a yellow suspension. The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and diluted with DCM. The organic layer were separated, then washed with water followed by saturated NaCl. The organic layer was dried over Na2SO4 and evaporated to a small volume, about 15 mL, from which a crystalline solid appeared which was collected, washed very sparingly with DCM and dried to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1 g, 66.6%) as a solid. LC-MS m/z 605.5 (M+H)+, 0.75 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][CH:47]1[CH2:52][C:51]([CH3:54])([CH3:53])[N:50]([CH3:55])[C:49]([CH3:57])([CH3:56])[CH2:48]1>CC(N(C)C)=O>[C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:46][CH:47]2[CH2:48][C:49]([CH3:56])([CH3:57])[N:50]([CH3:55])[C:51]([CH3:54])([CH3:53])[CH2:52]2)=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(=O)O)cc1
Agent: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Product: CN1C(C)(C)CC(NC(=O)c2ccc(NNC(=O)OC(C)(C)C)cc2)CC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(N′-tert-Butoxycarbonyl-hydrazino)-benzoic acid (4.452 g) in DMA (30 ml) was added disopropyl ethyl amine (6.16 ml) and HBTU (6.69 g) with stirring at room temp. 4-Amino-1,2,2,6,6-pentamethylpiperidine (3 g) was then added to the stirred solution. Stirring continued at room temp for 4 hrs.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>C(O)(=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:1]2[CH:15]=[CH:19][CH:18]=[CH:17]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: N#Cc1cc([N+](=O)[O-])ccc1-n1cccc1
Yield: 106.8 %

Procedure:
In a manner similar to Example 1, Step A, the reaction of 30.0 g (0.18 mole) of 2-amino-5-nitrobenzonitrile with 28.7 g (0.22 mole) of 2,5-dimethoxytetrahydrofuran in 60 ml of glacial acetic acid produced 41.0 g of 5-nitro-2-(1H-pyrrol-1-yl)benzonitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])(O)=O.[Na+]>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.COCCOC>[F:16][C:17]1[C:22]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
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: [Na+]
Solvent: COCCOC
Product: COc1cc2ncnc(-c3cccnc3F)c2cc1OC

Procedure:
4-Chloro-6,7-dimethoxy-quinazoline (250 mg, 1.11 mmol), 2-fluoropyridine-3-boronic acid (173 mg, 1.22 mmol), Pd(PPh3)4 (128 mg, 0.11 mmol), DME (4.0 mL) and 1 M NaHCO3 (1.0 mL) were reacted in a manner similar to Example 72. MS m/z=286 [M+1]+. Calc'd for C15H12FN3O2: 285.28.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[C:23](OS(C(F)(F)F)(=O)=O)[C:24]4[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:25]=4[N:26]=3)=[CH:16][CH:15]=2)=[CH:12][N:11]=[CH:10]1>O1CCOCC1>[CH2:1]([NH:8][C:23]1[C:24]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:25]=2[N:26]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]3[O:9][CH:10]=[N:11][CH:12]=3)=[CH:19][CH:18]=2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NCc3ccccc3)c2C1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Benzylamine (0.061 mL, 0.55 mmol) was added to tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.3 g, 0.55 mmol, Example 3c) in dioxane (4 mL) and the reaction mixture was stirred over night at 25° C. The solvent was removed under reduced pressure and the reaction mixture was redissolved in DCM and washed with water. The organic layer was dried (MgSO4), filtered and concentrated to give tert-butyl 4-(benzylamino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.238 g, 86%). MS (ESI+)/(ESI−) m/z 499/497
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][N:15]([CH3:28])[CH2:16][CH2:17][CH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:25]=O)[NH:22][C:23]=1[CH3:24]>N1CCCC1.C(O)C>[CH3:28][N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:25]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][CH2:2][OH:1])[NH:8][C:7]2=[O:13])[NH:22][C:23]=1[CH3:24]
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCO)c32)c(C)c1CCCN(C)C
Temperature: 90 °C
Yield: 98.1 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (177 mg, 1.0 mmol), 4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) and 3 drops of pyrrolidine in 2.0 mL of ethanol was refluxed at 90° C. for 4 hours and cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane, and dried in a vacuum oven overnight to give 360.6 mg (98%) of 3-[4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one.