Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:20])C(=O)C1.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])[N:23]=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])[N:23]=1
Reactant: Cc1nn(-c2ccccc2C#N)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Yield: 93.3 %

Procedure:
AIBN (141 mg, 0.857 mmol) and NBS (839 mg, 4.72 mmol) were added to a suspension of 2-(3-methyl-1H-indazol-1-yl)benzonitrile (1 g, 4.29 mmol) in CCl4 (20 mL) and the mixture heated to reflux for 2 h. The mixture was concentrated and the residue purified by silica gel chromatography to give the title compound (1.25 g, 93%) as an off white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[F:16][CH:15]([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([NH:18][C:19]3[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=3)=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: FC(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: Nc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: OCc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Temperature: 105 °C

Procedure:
To a mixture of 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30 (0.40 mmol) and (3-aminophenyl)methanol (0.40 mmol) in 1,4-dioxane (0.5 mL) is added p-TSA (0.4 mmol). The reaction mixture is heated at 105° C. for 2 days. After this time, the reaction mixture is diluted with a solution of 2M Na2CO3 (30 mL) and extracted with DCM (3×30 mL). The organic layer is washed with brine, dried over Na2SO4 and concentrated. Purification by short silica gel chromatography using a hexane:EtOAc=1:2 affords (3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)methanol 36. 1H NMR (400 MHz, d4-MeOH) δ 8.56 (s, 2H), 7.65 (m, 1H), 7.48-7.52 (m, 1H), 7.42-7.46 (m, 2H), 7.29 (t, J=8 Hz, 1H), 7.15-7.18 (m, 3H), 6.99-7.03 (m, 1H), 6.49 (t, J=73.6 Hz, 1H), 4.67 (s, 2H). MS (m/z) (M+1)+ 344.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][C:21]=3[F:36])[CH:16]=2)=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:54]1[CH:59]=[CH:58][C:57]([S:60]([CH:63]([CH3:65])[CH3:64])(=[O:62])=[O:61])=[CH:56][N:55]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:49]([O:48][C:46]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[CH:22][C:21]=3[F:36])[CH:16]=2)=[CH:13][C:12]([C:54]2[CH:59]=[CH:58][C:57]([S:60]([CH:63]([CH3:65])[CH3:64])(=[O:61])=[O:62])=[CH:56][N:55]=2)=[CH:11][N:10]=1)=[O:47])([CH3:51])([CH3:50])[CH3:52]
Reactant: CC(C)S(=O)(=O)c1ccc(Br)nc1
Reactant: CN(Cc1ccc(-c2cc(-c3cc(B4OC(C)(C)C(C)(C)O4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)c(F)c1)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4F)no3)c2)nc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl N-[[4-[5-[2-[bis(tert-butoxycarbonyl)amino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]isoxazol-3-yl]-3-fluoro-phenyl]methyl]-N-methyl-carbamate (322.6 mg, 0.3339 mmol) and 2-bromo-5-isopropylsulfonyl-pyridine (105.8 mg, 0.4007 mmol) in DMF (3 mL) was degassed and placed under an atmosphere of nitrogen. Pd(PPh3)2Cl2 (13.81 mg, 0.03339 mmol) was added and the reaction again degassed. 2M aqueous Na2CO3 (501.0 μL, 1.002 mmol) was added and the reaction was stirred at 95° C. for 2 hours. The reaction mixture was partitioned between EtOAc and brine and the aqueous layer extracted with EtOAc (×3). The combined organic extracts were washed with water (×3) and brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, loading with DCM and eluting with 0 to 50% EtOAc/Petroleum Ether) to give the impure sub-title compound as a yellow oil which was used in the next step without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:25][CH:24]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CCOC(=O)C1CNCCN1Cc1ccccc1
Product: CCOC(=O)C1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1Cc1ccccc1
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl 1-benzylpiperazine-2-carboxylate (Helv. Chim. Acta, 1962, 45, 2383) to give 1-benzyl-2-ethoxycarbonyl-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperazine in 67% yield.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6](OC)=[C:7](OC)[CH:8]=2)[N:3]=1.CC(O)=[O:19]>[OH-].[Na+].C1COCC1>[CH:7]1[CH:6]=[CH:5][C:4]2[N:3]=[CH:2][NH:11][C:10](=[O:19])[C:9]=2[CH:8]=1
Reactant: CC(=O)O
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=c1[nH]cnc2ccccc12
Temperature: 0 °C
Yield: 100 %

Procedure:
A solution of 2,4-dichloro-6,7-dimethoxy-quinazoline (2.12 g, 8.20 mmol) in 1 M NaOH (50 mL) and THF (15 mL) was stirred at room temperature under an argon blanket for 23 hours. The solution was cooled to 0° C., then acidified to pH 5 with AcOH. The resulting solids were collected by vacuum filtration and dried in a vacuum oven at 70° C. overnight to provide Intermediate 8 as a pale yellow powder (2.02 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ: 7.38 (s, 1H), 7.08 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.50–3.20 (br s, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17]O)[CH:14]=[CH:13][C:12]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:17][C:15]1[CH:14]=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([O:10][CH3:9])[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(CO)ccc1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.24 g (7.6 mmol) of NBS (N-bromosuccinimide) is added in small portions to a solution of (2-methoxy-biphenyl-4-yl)-methanol (1.35 g, 6.3 mmol) and triphenyl phosphine (2.0 g, 7.0 mmol) in 15 mL of CH2Cl2 at 0° C. The cooling bath is removed and the reaction mixture is stirred at room temperature overnight. The reaction mixture is then concentrated in vacuo, and the residue is purified by chromatography on silica gel (10% EtOAc/hexane) to furnish 4-bromomethyl-2-methoxy-biphenyl as a clear, colorless oil. 1H NMR (250 MHz, CDCl3) δ 7.45-7.55 (m, 2H), 7.20-7.45 (m, 4H), 7.05 (dd, 2H), 7.0 (d, 1H), 4.50 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [ClH:1].O.[H][H].[N:5]1([CH:11]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[ClH:1].[N:5]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C1CC(N2CCOCC2)CCN1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A stirred mixture of Pd(OH)2 (20% on carbon (<50% wet), 390 mg, 25 wt %), methanol (50 mL), and ≦1.7 M HCl (3 eq, ˜10.6 mL—including water added later when ppt was seen) under nitrogen was exchanged to 1 atm. hydrogen atmosphere by flushing (˜20 sec) using a balloon of nitrogen into the vessel and out through an oil bubbler. After 20 min. the reaction mixture under hydrogen was heated to 50° C. and 4-(morpholin-4-yl)-1-benzylpiperidine (1.56 g, 6.0 mmol) in methanol (8 mL) was added dropwise over 30 min. After 10 h, tlc indicated all starting amine was consumed to a more polar spot (ninhydrin active). The reaction mixture was then filtered through Celite and evaporated to yield the 4-(morpholin-4-yl)piperidine dihydrochloride as an off-white solid. This material was subjected to free-basing using excess basic resin (>16 g, Bio-Rad Laboratories, AG 1-X8, 20-50 mesh, hydroxide form, methanol washed two times) and a methanol mixture of the amine hydrochloride. After swirling with the resin for 30 min., the methanol solution was decanted and evaporated to yield 932 mg of 4-(morpholin-4-yl)piperidine free base as a waxy crystalline solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:23])[C:20](=[O:22])[O-:21])[S:16]2)[C@@H:12]([OH:24])[C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:23])[C:20](=[O:21])[O:22][C:4]([CH3:7])([CH3:6])[CH3:5])[S:16]2)[C@@H:12]([O:24][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C@@H:11]1[O:25][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1ccc(CBr)cc1
Reactant: CN(C(=O)[O-])C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C(=O)OC(C)(C)C)S[C@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.5 %

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-5-((tert-butyldimethylsilyloxy)methyl)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(methyl)carbamate (20 g, 45 mmol) in DMF (150 mL) was added sodium hydride (10.7 g, 446 mmol) in portion at 0° C., and followed by addition of 1-(bromomethyl)-4-methoxybenzene (36 g, 179 mmol). The resulting solution was stirred for 2 h at room temperature, quenched with cold water (200 mL), and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (5×200 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to afford a residue, which was purified by silica gel column, eluted with 10% ethyl acetate in petroleum ether to give compound 27 as a yellow liquid (21 g, 68%). (ES, m/z): [M+H]+ 689.1. 1H NMR (300 MHz, CDCl3) δ 7.31-7.37 (m, 2H), 7.22-7.28 (m, 2H), 6.10-6.12 (d, J=6.9 Hz, 1H), 4.60-4.74 (m, 4H), 4.20-4.47 (m, 4H), 3.82 (s, 6H), 3.69 (s, 3H), 3.33-3.37 (m, 2H), 1.56 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26](Cl)[N:25]=[C:24]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C>CS(C)=O>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:25]=[C:24]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:23]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: OCCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCCO
Yield: 67.9 %

Procedure:
1,3-Propanediol (580 mg) was dissolved in dimethyl sulfoxide (15 ml). Sodium hydride (297 mg) and 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyl]benzenesulfonamide (1.1 g) were added to the solution. The resultant mixture was stirred for 4 hours at 120° C. Ethyl acetate was added to the reaction mixture, followed by successive washing with 0.5N-HCl, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1), to thereby obtain 802 mg (yield: 68%) of the title compound as a white powder.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]([O:6][CH3:7])=[O:5].[NH:8]1[CH2:11][CH2:10][CH2:9]1>C(#N)C>[N:8]1([CH2:3][C@H:2]([OH:1])[C:4]([O:6][CH3:7])=[O:5])[CH2:11][CH2:10][CH2:9]1
Reactant: C1CNC1
Reactant: COC(=O)[C@@H]1CO1
Solvent: CC#N
Product: COC(=O)[C@@H](O)CN1CCC1
Temperature: 100 °C
Yield: 100 %

Procedure:
(S)-Methyl oxirane-2-carboxylate (1475 mg, 14.45 mmol) in acetonitrile (2 mL)was added to azetidine (825 mg, 14.45 mmol) in acetonitrile (8 mL). The reaction was heated to 100° C. for 60 minutes in the microwave reactor and cooled to room temperature. The mixture was evaporated to afford the crude product (2.3 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:17][C:16]3[CH2:15][CH:14]([C:18]([O:20]CC)=[O:19])[C:13]4=[N:23][NH:24][N:25]=[C:11]([C:12]=34)[C:10]([S:26][CH3:27])=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:17][C:16]3[CH2:15][CH:14]([C:18]([OH:20])=[O:19])[C:13]4=[N:23][NH:24][N:25]=[C:11]([C:12]=34)[C:10]([S:26][CH3:27])=[N:9]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1CC2=C3C(=NNN=C31)C(SC)=NN(Cc1ccc(OC)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN2CC3=C4C(=NNN=C4C(C(=O)O)C3)C(SC)=N2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The crude ethyl 6-(4-methoxybenzyl)-4-(methylthio)-6,7,8,9-tetrahydro-2H-1,2,3,5,6-pentaazabenzo[cd]azulene-9-carboxylate (24 g), was dissolved in ethanol (250 mL) and sodium hydroxide (27.11 g, 677.75 mmol) in water (250 mL) was added to it. The reaction mixture was then stirred at 60° C. for 2 h. Ethanol was removed under reduced pressure and the aqueous layer was acidified using 10% citric acid solution. The aqueous layer was then extracted with dichloromethane (250 mL×3); the combined organic layer was washed with water (500 mL×2) followed by brine (500 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a residue as 6-(4-methoxybenzyl)-4-(methylthio)-6,7,8,9-tetrahydro-2H-1,2,3,5,6-pentaazabenzo[cd]azulene-9-carboxylic acid. To the residue (24 g) was added 4M HCl indioxane—(500 mL) and the mixture was refluxed for 16 h. Solvent was removed under reduced pressure and saturated NaHCO3 solution (250 mL) was added to the residue. The mixture was then extracted using dichloromethane (200 mL×3). The combined organic layer was washed with water (500 mL), brine (500 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (using 0-10% tetrahydrofuran in dichloromethane) to give a solid and the solid was further titurated with n-pentane to provide pure 6-(4-methoxybenzyl)-4-(methylthio)-6,7,8,9-tetrahydro-2H-1,2,3,5,6-pentaazabenzo[cd]azulene (6.0 g, 29.2% yield over four steps). LCMS [M+H]: 342, HPLC: 97.65% (254 nm), 1H NMR (DMSO-d6, 400 MHz): δ 12.97 (bs, 1H), 7.24 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 4.91 (s, 2H), 3.72 (s, 3H), 3.55 (d, J=7.2 Hz, 2H), 2.90-2.80 (m, 2H), 2.45 (s, 3H), 2.0-1.9 (m, 2H).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH3:31][NH2:32]>C(#N)C>[CH3:31][NH:32][C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1
Reactant: CN
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Solvent: CC#N
Product: CNc1oc2c(O)c(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (20 mg, 0.066 mmol) in acetonitrile (3 mL) was added the solution of methyamine (1 mL, excess as reactant and base), and the reaction mixture was stirred at room temperature for 1 hour when the precipitates appeared. The solvent was distilled under vacuo and the crude was dissolved in tetrahydrofuran (2 mL), 1M hydrochloric acid (1 mL) was added and the reaction mixture was stirred for 1 hour then diluted with dichloromethane (10 mL) and washed with water. The organic layer was dried over magnesium sulfate and solvent was distilled under vacuo. The crude was purified by PTLC (eluent=Hexane:ethylacetate:triethylamine; 2:8:1%) to gave the title compound as a yellow-green solid (5 mg, 29%); 1H NMR (300 MHz, CDCl3) δ 8.91 (broad, 1H, NH), 6.93 (s, 2H, benzoyl Hs), 6.59 (d, 1H, J=8.56 Hz), 6.46 (d, 1H, J=8.51 Hz), 5.61 (bs, 1H, OH), 3.91 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe), 3.28 (d, 3H, J=5.28 Hz).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30][O:31]CC4C=CC=CC=4)[C@@H:25]([OH:40])[C@H:24]3[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:15]=2)[CH2:10]1>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30][OH:31])[C@@H:25]([OH:40])[C@H:24]3[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:15]=2)[CH2:10]1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate (0.022 g, 0.03 mmol) in ethanol (2 ml) under an atmosphere of Argon is treated with palladium hydroxide on carbon (0.05 g, 20% w/w carbon). The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature for 30 hours and then filtered through Celite™. The filtrate is concentrated in vacuo and purification of the crude by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water −0.1% TFA) yields the title product. (MH+ 573.4)
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][C:11]2[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=2)[O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:23])[C:20](=[NH:22])[NH2:21])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[S:27](Cl)Cl>CN(C=O)C>[NH2:22][C:20]1[C:19]([NH:18][CH2:17][CH2:16][CH2:15][O:14][C:13]2[CH:24]=[CH:25][CH:26]=[C:11]([CH2:10][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:12]=2)=[N:23][S:27][N:21]=1
Reactant: N=C(N)C(=N)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: ClSCl
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1nsnc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride (854 mg; 2 mmoles) in 6 mL of DMF under N2 in an ice bath was added SCl2 (206 mg; 2 mmoles) in 2 mL of DMF. The reaction mixture was stirred at ambient temperature and the title compound was produced.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH2:17]Br)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:14][C:12]([CH:11]1[CH2:17][NH:1][C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=2[O:9]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(Br)CBr
Reactant: Nc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2cc(Br)ccc2O1
Yield: 78.2 %

Procedure:
A mixture of 2-amino-4-bromophenol (5.00 g, 26.6 mmol), ethyl 2,3-dibromo-propionate (7.84 g, 29.2 mmol), and potassium carbonate (10.3 g, 81.8 mmol) in acetone (55 mL) was heated at reflux for 16 h. After evaporation of volatile material, the residue was partitioned between dichloromethane and water. The organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient produced 6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester (5.95 g, 78%). Orange solid, MS (ISP)=286.0 (M+H)+.
Reaction SMILES: C(NC(NC1C=CC([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[N:21]([CH3:22])[N:20]=[CH:19][C:17]=3[N:18]=2)=CC=1)=O)C.[N+:30]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[CH3:29][C@H:24]1[CH2:25][O:26][CH2:27][CH2:28][N:23]1[C:15]1[C:16]2[N:21]([CH3:22])[N:20]=[CH:19][C:17]=2[N:18]=[C:13]([C:36]2[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:38][CH:37]=2)[N:14]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3c(cnn3C)n2)cc1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc([N+](=O)[O-])cc2)nc2cnn(C)c12

Procedure:
This compound was prepared in an analogous fashion to (S)-1-ethyl-3-(4-(1-methyl-7-(3-methylmorpholino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)urea, using 4-nitrophenylboronic acid pinacol ester as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 8.62 (d, J=9.0 Hz, 2H), 8.32 (d, J=9.0 Hz, 2H), 8.22 (s, 1H), 4.27 to 4.17 (m, 4H), 4.08 to 3.95 (m, 2H), 3.93 to 3.82 (m, 1H), 3.79 to 3.67 (m, 2H), 3.60 to 3.50 (m, 1H), 1.38 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][CH2:10][C:11]([NH:13][CH2:14][C@H:15]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)[CH3:16])=[O:12]>>[OH:9][CH2:10][C:11]([NH:13][CH2:14][C@H:15]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)[CH3:16])=[O:12]
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1O
Reactant: ClCc1ccccn1
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1OCc1ccccn1
Yield: 29 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide to give the title compound as a white solid in 29% yield; NMR spectrum (DMSO-d6) 1.40 (d, 3H), 2.27 (s, 3H), 3.43 (dt, 1H), 3.72 (dt, 1H), 3.80 (d, 2H), 4.94 (m, 1H), 5.20 (s, 2H), 5.46 (t, 1H), 7.00 (d, 1H), 7.21 (d, 1H), 7.30 (d, 1H), 7.34 (dd, 1H), 7.56 (m, 3H), 7.68 (t, 1H), 7.85 (td, 1H), 8.16 (t, 1H), 8.43 (s, 1H), 8.58 (d, 1H), 9.94 (s, 1H); Mass spectrum MH+ 474.